OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Although many targeted anticancer therapies have become available over the past several decades, chemotherapy remains the cornerstone of treatment for many types of cancer. Despite the widespread availability of antiemetic regimens, between 30% and 50% of patients receiving chemotherapy experience treatment-related nausea and/or vomiting.

 Poorly controlled chemotherapy-induced nausea and vomiting (CINV) increases the risk of treatment delays, treatment discontinuation, and hospitalization.

 It is also one of patients’ biggest concerns during chemotherapy and significantly affects their quality of life.

Antiemetic Guidelines and Barriers to Care

, Lee S. Schwartzberg, MD, FACP, moderated a Peer Exchange panel on the management of CINV. All the panelists have substantial knowledge of and experience with CINV; Schwartzberg, Dawn Dolan, PharmD, BCOP, and Eric Roeland, MD, were members of the National Comprehensive Cancer Network (NCCN) panel that updated the NCCN antiemesis guidelines in March 2017. The panelists discussed how to ensure that more patients undergoing chemotherapy receive optimal antiemetic regimens, their own approaches to managing CINV, and some of the more recently approved antiemetics.

The American Society of Clinical Oncology (ASCO), NCCN, and the Multinational Association of Supportive Care in Cancer/European Society of Medical Oncology have all published evidencebased antiemetic guidelines, which they routinely update (Table). “We have great guidelines now,” said Schwartzberg, who noted that they are all similar. The guidelines identify which drugs are highly emetogenic chemotherapy (HEC) or moderately emetogenic (MEC). “HEC is typically considered to induce nausea in more than 90% of the population if you were not to give any prophylactic antiemetics...MEC induces emesis in 30% to 90% if you were not to give antiemetics,” Dolan said. She praised the reclassification of carboplatin and cisplatin from MEC to HEC in the guidelines.

Table. Emetic Risk Levels for Antineoplastic Agents

“I have a little bit of a problem with the way the categories are laid out; 90% or more is highly emetogenic but 89% is not,” said panelist Howard Levine, PharmD. The risk of emetogenicity is used to guide choice of prophylaxis. The panel agreed that since many antiemetics are available, the goal should be to prevent CINV in all patients by using the most effective agent first—even if the chemotherapy agent has a low risk of emesis.

Roeland pointed out that the guidelines stratify chemotherapy solely by risk of vomiting, whereas nausea is more prevalent. Supporting Roeland’s point, a survey of 386 patients about their most recent cycle of chemotherapy found that 60% experienced nausea only and 18% experienced vomiting with or without nausea.

 He emphasized the need to consider patient factors that increase the risk of nausea with chemotherapy, which in women includes younger than 50 years, a history of motion sickness or pregnancy-induced nausea and vomiting, and low alcohol intake. The greatest risk factor for all patients is CINV with a previous cycle of chemotherapy. “If you had CINV in your first cycle, you were 4 to 5 times more likely to have CINV in subsequent cycles,” Roeland said. Beth Eaby-Sandy, CRNP, OCN, said the guidelines help but that it remains difficult to predict who will experience CINV. “Know your patient, do a thorough review of systems and history and understand what is causing their nausea besides the drug that you’re giving them, and then tailor your approach to managing it based on the patient,” she recommended.

Nonadherence to the guidelines remains a barrier to optimal management of CINV, which can be broken down into acute phase, delayed phase, breakthrough, and anticipatory. “Acute CINV is defined as the first 24 hours after the treatment... from 2 days out after treatment, it becomes the delayed phase,” Levine explained. He described breakthrough as nausea or vomiting that occurs despite appropriate use of antiemetic therapy, which he said can occur any time from day 1 through day 5. Anticipatory CINV occurs before treatment is administered. Levine said it might be triggered by a smell or sight or, in many cases, by the expectation that chemotherapy causes nausea. “We actually do a pretty good job of controlling acute nausea and vomiting...but the delayed phase is really where the challenge has been,” he said.

A survey of more than 500 US oncology nurses in 2015 found that although most nurses expressed familiarity with NCCN or ASCO antiemetic guidelines, adherence was inconsistent.

While high proportions of respondents felt the antiemetics used in their practices were adherent to guidelines for acute and delayed CINV phases in the MEC setting (85% and 91%, respectively), adherence rates for prescribing patterns were much lower in the HEC setting in both phases (73% and 25%, respectively).

Levine said another obstacle is that physicians are more interested in treating the cancer than addressing CINV. Accordingly, his practice has shifted much of the responsibility for managing CINV from the physicians to physicians’ assistants, nurses, and pharmacists, and Levine said the change improved management of CINV dramatically. Roeland said part of the problem is that physicians have difficulty keeping up with the pace of change in the oncology field. “Having a team-based approach is the way to go,” Roeland said.

Eaby-Sandy said her facility, like many others, has a multidisciplinary team to maintain specific order sets in the electronic medical record that pair the appropriate antiemetics with each chemotherapy regimen. “I think that fosters adherence with the guidelines because if they’re prebuilt, then you’re building them as part of the guidelines,” she said.

Dolan questioned whether using prebuilt order sets might make clinicians too complacent. “We fired off the order, everything is kind of already in there, and so it doesn’t lend itself to having to think about the more individualized approach,” she said. The panel also talked about the importance of patient education in CINV management. Roeland said it was important to inform patients and caregivers “that they’re not to expect nausea.” He said movies and the media may have fostered the popular perception that nausea means your chemotherapy is working but that is not the case. “We have tools available for patients,” he said. Dolan said it is also important to encourage patients to inform their provider when they feel nausea with chemotherapy. “I always tell patients there are no points for bravery,” she said.

Schwartzberg said oncologists need to remind patients “to tell us everything” because there are ways to deal with nausea without compromising the chemotherapy regimen. Dolan recommended the NCCN patient guide, which now includes a mobile app. She said the guide “provides a lot of good information for patients [and] is easy to read.” Dolan also recommended that someone from the healthcare team call patients after chemotherapy to ask them how they are feeling.

Guidelines agree that preventing CINV is easier than treating it, and they recommend starting with the most effective regimen first. “Unfortunately, some payers use something called step therapy, which basically mandates that patients should get sick before they get the optimal regimen. I don’t think that’s an appropriate approach,” Schwartzberg said. Controlling CINV in the delayed phase is the greatest unmet need, and many of the newer antiemetic agents have longer half-lives to prolong their efficacy.

Most of the antiemetic regimens recommended for HEC combine a neurokinin 1 (NK1) receptor agonist (RA) with a 5-HT3 RA and dexamethasone. Dolan said first-generation 5-HT3 RAs include ondansetron, dolasetron (Anzemet), and oral granisetron. Palonosetron and subcutaneous (SC) granisetron are second-generation 5-HT3 RAs. “Early first-generation 5-HT3 RAs typically have a shorter half-life; they’re pretty good for preventing acute nausea but not so great in the delayed phase,” she said. In comparison, Dolan said palonosetron and granisetron SC have much longer half-lives and greater binding affinity for the 5-HT3 receptor. “They definitely have higher efficacy rates compared with the first-generation 5-HT3 antagonists,” she said. Adding dexamethasone improves the efficacy of 5-HT3 RAs. Dolan said oral and intravenous 5-HT3 RAs are equally effective.

The NK1 RAs were introduced after 5-HT3 RAs. Eaby-Sandy said that combining an NK1 RA with a 5-HT3 RA “dramatically improved control [of CINV] in the delayed setting” because of how long NK1 RAs bind to substance P, a neurotransmitter that stimulates vomiting pathways in the brain. Newer NK1 RAs such as rolapitant (Varubi) and netupitant bind longer to substance P than first-generation NK1 RAs such as aprepitant and fosaprepitant (an intravenous [IV] form of aprepitant).

“Rolapitant has a much longer half-life, so that can be dosed on day 1 and have coverage up to 7 days or even longer,” she said. The FDA approved an oral formulation of rolapitant in September 2015. In October, the agency granted approval for its use in combination with other antiemetic agents to treat delayed CINV in adults.

Schwartzberg, who was involved in the pivotal phase III multicenter trials of oral rolapitant, said it performed well in adults with cancer who received HEC or MEC.

In 2 of the trials, patients scheduled to undergo their first cycle of highly emetogenic cisplatin-based chemotherapy were randomly assigned to prophylaxis with oral rolapitant or placebo; patients in both cohorts also received granisetron SC and dexamethasone.

The trial defined complete response (CR), which was the primary endpoint, as no emesis or need for rescue medication more than 24 to 120 hours after cycle 1. In a pooled analysis, significantly more patients in the rolapitant group than in the placebo group achieved a CR (71% vs 60%, respectively; 

In a randomized phase III trial of patients receiving MEC containing an anthracycline plus cyclophosphamide, patients were randomly assigned to oral rolapitant or placebo, as well as oral granisetron and dexamethasone.

 The primary endpoint was again CR in the delayed phase. The CR rate was 71% in the rolapitant arm versus 62% in the placebo arm (

 Rolapitant was well tolerated, and none of the studies reported any serious treatment-emergent adverse events or deaths.

The approval for the IV formulation was based on a bioequivalence trial that showed the comparability of the IV and oral formulations. The bioequivalence study randomized healthy volunteers to a single dose of 166.5 mg of IV rolapitant administered over 30 minutes (n = 61) or 180 mg of oral rolapitant (n = 62). Bioequivalence was defined by estimating whether the 90% confidence intervals for the ratio of the area under the curves of the 2 formulations were entirely included within the acceptance range of 80% to 125%, according to Tesaro, the company developing the drug.

In 2014, the FDA approved NEPA (Akynzeo), which is an oral fixed-dose combination of the NK1 RA netupitant (300 mg) plus palonosetron. Approval was based on results of clinical trials in chemotherapy-naïve patients scheduled for HEC or MEC.

In a dose-finding trial, patients received NEPA or palonosetron monotherapy; all patients received dexamethasone. The study defined CR as no emesis or rescue medication for up to 120 hours after administration of cisplatin-based chemotherapy.6 The CR rate in the NEPA 300-mg arm was 90% compared with 77% in the palonosetron-only arm (

 NEPA was also superior to palonosetron at controlling nausea during the acute phase.

In a phase III trial of NEPA, patients scheduled to receive MEC were randomly assigned to prophylaxis with NEPA 300 mg or a single dose of palonosetron; both arms received dexamethasone.

 In this trial, CR was defined as no emesis or rescue medication for 25 to 120 hours after chemotherapy administration. Patients in the NEPA arm were significantly more likely to achieve CR than patients in the placebo arm (74% vs 67%; 

 “In general, we’re seeing that the NK1 RAs really don’t add an incremental increase in toxicity,” Dolan said.

Eaby-Sandy shared the story of a patient whose insurance company would not authorize NEPA unless the patient first failed aprepitant or fosaprepitant and ondansetron. She referred the insurer to the NCCN guidelines but “they did not budge.”

Schwartzberg criticized the insurer’s decision as arbitrary and said it did not make sense. The panel discussed how in the United States it is far more difficult to get approval for oral antiemetics than IV ones even though, as Roeland pointed out, the efficacy is equal.

Another antiemetic regimen recommended as equal to the others in the NCCN guidelines combines olanzapine (Zyprexa), palonosetron, and dexamethasone.8

Roeland said, “Olanzapine has been used in the treatment of schizophrenia and bipolar disorder at high doses over chronic periods of time.” Olanzapine, an antipsychotic, has several targets, including multiple serotonin and dopamine receptors, said Roeland.

In a randomized phase III trial, olanzapine was compared with placebo; both regimens included dexamethasone, aprepitant, or fosaprepitant, and a 5-HT3 RA.

 Investigators “chose a primary endpoint of no nausea, which I think all of us would agree is probably the most clinically meaningful endpoint as we move forward,” Roeland said. In the first 24 hours after chemotherapy, 74% of patients in the olanzapine arm had no nausea compared with 45% in the placebo arm (

Olanzapine also controlled nausea significantly better than placebo in the delayed phase (

 = .002). The most common adverse effect was sedation, which peaked on day 2.9 Olanzapine is typically administered the night before chemotherapy, and Levine expressed concern that some patients might forget to take it.

Articles

Despite the widespread availability of antiemetic regimens, between 30% and 50% of patients receiving chemotherapy experience treatment-related nausea and/or vomiting.

Experts Discuss Ways to Remove Barriers to Optimal Management of CINV

There are certain commonly used terms in the realm of oncology that may result in unintended consequences and should be considered carefully before being employed in conversation or in writing. When it comes to words clinicians use in talking with patients and their families, that list starts with the word “cure.” Of course, we know this word means the cancer is gone and will never return.

But when is it appropriate to declare that “the cancer is cured” for an individual? Surely, physicians today understand that the absence of evidence of disease at some arbitrarily defined point in time (eg, 5-year progression-free survival) does not equate with this hoped-for outcome, although it is certainly the case that the longer a patient goes without experiencing recurrence, the greater the probability that the end result will be a “cure.” In fact, cure can only be declared objectively in many advanced cancers after very extended periods of follow-up or when death occurs from a cause not related to cancer in the absence of signs of the malignancy.

Yet one of the most common questions that oncologists hear from patients must be, “Am I cured?” It is difficult to provide an objectively valid answer to this question, for as much as one may wish to definitively answer “yes,” the evidence in a given clinical setting may strongly suggest the danger associated with prematurely stating what that patient and family yearn to hear. As a result, great caution is advised when discussing the concept of a cure with a patient following a cancer diagnosis and in carefully distinguishing expressions such as “you are hopefully cured” or “you have a good chance of being cured” from the definitive “you are cured.”

Another term fraught with the potential for serious misinterpretation is the increasingly used expression “actionable” in reference to molecularly defined abnormalities within a patient’s cancer. It is common practice these days for commercial molecular laboratories to accompany their list of observed genomic findings with a statement that “action” is possible against 1 or more abnormalities. The problem is that the definition of “actionable” used by these entities is often substantially different from what might be considered reasonable by an objective external observer.

For example, does the existence of a small phase I trial with strict eligibility criteria for evaluating a novel antineoplastic agent in the molecular abnormality in question at a single academic institution more than 1000 miles from the patient’s home really make a genomic finding “actionable”? And if the patient is willing to undertake the journey, has insurance that will cover the costs of standard-ofcare charges, and meets all other eligibility criteria except for a prior history of a completely unrelated and inconsequential “benign tumor,” what can be said about the validity of the “actionable” claim?1 How can the abnormality be considered “actionable” if the patient realistically is unable or not permitted to act? The negative impact associated with the current usage of this terminology on the emotional and psychological well-being of such patients needs to be considered more carefully.

Next, we turn to the term “conflict of interest,” which is commonly used to describe a clinician or clinical investigator who has received financial payment from a commercial interest (eg, pharmaceutical, biotech, device company) for specific services such as advising on clinical trial design or serving as a member of a data safety and monitoring committee or a medical advisory committee. Although use of the expression without an additional modifier, such as “possible” or “potential,” may imply to some the existence of an actual conflict of interest, the mere listing of an individual’s name and the organizations providing payment is not problematic in most circumstances.

However, this poorly defined terminology can also serve as a platform for what might appear to be a disquieting and otherwise unsubstantiated insinuation that industry is paying for influence, as in a recent publication in which the authors state that “these results raise the question of whether the industry pursues highly influential physicians or whether the acceptance of financial conflict improves one’s academic output through publications derived from collaboration.”

Finally, there are several expressions commonly utilized by certain academics who continue to contend that the FDA is inappropriately approving novel antineoplastic strategies in the absence of evidence of “clinical benefit.” To these authors, the gold standard defining clinical benefit of a new cancer drug is solely the result of a double-blind placebo-controlled randomized phase III trial that demonstrates a statistically significant improvement in overall survival. Using a surrogate measure for clinical benefit, as defined by these academic purists, fails the test of being definitive.

Such was the case in a recent paper published in a high-impact medical journal that highlighted the use of surrogate measures as outcomes and suggested this was a less-than-acceptable standard.

 The authors maintained that “drugs granted accelerated approval quickly became standard of care despite the limited evidence on which they were approved.” This statement was made despite the fact that the evidence might have included major objective response rates, substantial improvement in cancer-related symptoms, or prolongation of progression-free and symptom-free survival in comparison with the existing standardof-care through a nonrandomized or randomized experience. But in each case a surrogate endpoint was employed in the regulatory decision to permit a drug to be commercially available.

The use of these words in this manner directly implies a lack of meaningful clinical utility for the agent. Rather than rely upon academic commentators to define “clinical benefit,” perhaps the decision about what should be considered an acceptable measurable outcome should be left to patients themselves.

. Zikmund-Fisher BJ. When “actionable” genomic sequencing results cannot be acted upon. 

 Oncol. 2017;3(7):891-892. doi: 10.1001/ jamaoncol.2016.3283.

Lammers A, Edmiston J, Kaestner V, Prasad V. Financial conflict of interest and academic influence among experts speaking on behalf of the pharmaceutical industry at the US Food and Drug Administration’s Oncologic Drugs Advisory Committee meetings. 

 2017;92(7):1164-1166. doi: 10.1016/j.mayocp.2017.04.014.

Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. 

. 2017;318(7):626-636. doi: 10.1001/jama.2017.9415.

. PEBC’s Ovarian Oncology Guidelines Group. A systematic review of patient values, preferences and expectations for the treatment of recurrent ovarian cancer. 

2017;146(2):392-398. doi: 10.1016/j.ygyno.2017.05.039.

There are certain commonly used terms in the realm of oncology that may result in unintended consequences and should be considered carefully before being employed in conversation or in writing.

Some Common Oncology Terms Carry Unanticipated Consequences

Marcela V. Maus, MD, PhD, is an expert in the field of cellular immunotherapy, serving as director of research activities in cellular immunotherapy at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School.

How do the various CAR T-cell therapies in clinical development differ in their mechanism of action and targets?

How is CAR T-cell therapy shaping the treatment of hematologic malignancies?

What are the inherent challenges in developing this type of therapy for solid tumors?

What are the implications of the recent FDA approval of tisagenlecleucel?

The work in her own lab seeks to design and evaluate the next generation of chimeric antigen receptor (CAR) T cells in both hematologic malignancies and solid tumors, with the goal of improving safety and efficacy, in addition to understanding how CAR T cells might be used as delivery vehicles for other drugs.

There are 4 basic parts to a CAR T-cell therapy: the type of T cell used (CD4/CD8/other subsets), the vector used to introduce the genes that encode the CAR, the genes that encode the CAR itself, and the culture system used to grow the T-cell product. Each of these can differ in each product, but most think about what the CAR itself will target. The CAR T cells that are closest to commercialization, and the 2 that were recently approved, all target the B-cell marker CD19. There are many other CAR targets in development, as well, and promising data have been presented with CAR T cells targeting the B-cell maturation antigen, a marker that is frequently present in multiple myeloma. 

CAR T cells are a revolutionary form of personalized therapy for hematologic malignancies; they have a completely different mechanism of action from chemotherapy or radiation therapy, and they are different from small molecule drugs. Although at first they will be approved in the relapsed or refractory setting, there is potential for this kind of therapy to move up to earlier lines of treatment. 

Solid tumors seem to be more challenging for CAR T cells because we don’t have as well-defined targets to direct the CARs to and because they have a robust inhibitory microenvironment that can turn CAR T cells off. However, I think both of these are potential avenues of research to develop effective CAR T cells for solid tumors.

The new approval means that patients will no longer have to wait for the availability of a slot on a protocol, and they won’t technically be participating in an experimental approach. It will be prescribed by their doctor, although there are still limitations on which doctors and hospitals will have the therapy available, and it will still involve coordination to make the cell products.

How are gene-editing technologies playing a role in the development of CAR T-cell therapy?

Also, now instead of being paid for by the company (Novartis, in this case), it will be paid for by the patient’s insurance. The cost of the treatment seems high when you look at it in isolation, but given the complexity of manufacturing an autologous product for each individual patient, and the value that it brings, it is less than some were expecting. It is also interesting that Novartis has agreed to a model where they will be paid only if the patient has a response and will assume the risk and cost if the patient does not respond. 

Gene-editing technology offers new and intriguing possibilities for next-generation CAR T cells: Some companies are developing “off the shelf” CAR T cells, so that one batch of cell products stored in the freezer could be used on demand to treat any patient in need. Others are also developing souped-up T cells that can have the CAR genes integrated into specific genes in the host chromosome or that knock out some of the checkpoint molecules that can turn off T cells. We are in exciting times in this research, and hopefully more and more patients will benefit from these advances in cellular immunotherapy.

Marcela V. Maus, MD, PhD, evaluates the next generation of chimeric antigen receptor (CAR) T cells in both hematologic malignancies and solid tumors

Cellular Immunotherapy Expert Explains CAR T-Cell Therapy Excitement

Chimeric antigen receptor (CAR) T cells have hit prime time, with the 2 recent FDA approvals for this class of cell-based therapy. Undoubtedly this option will be a game changer for patients with B-cell malignancies who have only a small number of available treatment options; however, questions regarding the real-world utility of CAR T-cell therapies remain. Several challenges may affect the adoption of CAR T-cell therapy, which range from logistical complexities of therapeutic development to the potentially fatal toxicities of treatment.

It will be several years before the true impact of CAR T cells becomes apparent, but it is increasingly evident that long-term clinical success requires unlocking the potential of CAR T-cell therapy beyond B-cell malignancies, particularly in solid tumors, which account for the vast majority of cancer deaths.

A number of innovations are already entering the scene, including next-generation “armored” CARs and the application of state-of-the-art genome-editing technologies.

CAR T-cell therapy falls under the banner of adoptive cellular therapy (ACT), in which the effector cells of the immune system, predominantly the T cells, are transplanted into a patient. The graft-versus-tumor effect observed in patients undergoing allogeneic hematopoietic stem cell transplantation served as the stimulus for pursuing ACT. T cells present in the transplanted material were seemingly capable of mounting an effective antitumor immune response, but this was limited by the development of graft-versus-host disease (GVHD), wherein the transplanted T cells also attacked healthy tissue, causing severe toxicity.

Genetically modifying host T cells to endow them with tumor-killing specificity originated in the 1980s. Seminal studies demonstrated that replacing the region of the T-cell receptor (TCR) responsible for antigen recognition with the singlechain variable fragment (scFv) of an antibody could couple antibody specificity for a tumor-associated antigen (TAA) with the T-cell activating machinery of the TCR.

 This permitted direct activation of T cells by tumor cells that express the target antigen, in a manner that bypasses the need for antigen presentation by the major histocompatibility complex.

The prototypical CAR was composed of an extracellular portion, consisting of the antibody scFv, joined to a hinge or spacer and then a transmembrane domain that spans into the cell and links to an intracellular signaling region.

The latter mediates T-cell activation and was most often derived from the CD3ζ chain of the TCR, which harbors 3 immunoreceptor tyrosine-based activation motifs (ITAMs). When the CAR engages its target antigen, the ITAMs become phosphorylated and serve as adaptors for a panel of signaling proteins that coordinate T-cell activation and proliferation.

CAR T cells are generated by collecting host T cells through leukapheresis, where the CAR is introduced to the T cells through a viral vector. Clinical trials of the resulting CAR T cells, which can then be infused back into the patient, were pioneered by investigators at Memorial Sloan Kettering Cancer Center and the University of Pennsylvania.

Figure. Mechanism of Action of CAR Therapies

Several subsequent generations of CARs have been developed to improve on the efficacy of the first generation. The realization that full activation of T cells required 2 signals led to the incorporation of costimulatory domains in secondand third-generation CARs, with enhanced T-cell activity and persistence and greater antitumor efficacy.

In this rapidly evolving field of immuno-oncolytic therapeutic development, the most clinically advanced CAR T cells are currently those engineered against CD19, a cell surface receptor constitutively expressed on tumors in hematologic malignancies. Several pharmaceutical companies raced to be the first to secure regulatory approval, but ultimately the first-to-market advantage went to Novartis’ tisagenlecleucel (Kymriah).

In August, tisagenlecleucel was approved for the treatment of pediatric and young-adult patients (up to 25 years) with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL). The efficacy and safety of tisagenlecleucel were demonstrated in the phase II ELIANA trial that led to its indication. A total of 68 pediatric and young-adult patients with CD19-positive B-cell precursor ALL were infused with a single dose of CAR T cells. After a follow-up of 3 months, 63 patients treated with tisagenlecleucel were evaluable for response; 83% achieved complete remission (CR) or incomplete CR within 3 months of infusion with minimal residual disease (MRD)—negative status achieved in the bone marrow.

Hot on Novartis’ heels is Kite Pharma, whichgained the FDA’s approval in October for its CD19-targeted CAR T-cell therapy, axicabtagene ciloleucel (axi-cel; Yescarta). The drug is indicated for the treatment of patients with certain types of aggressive relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). The approval was based on findings from the ZUMA-1 trial.

As of January 2017, 101 patients enrolled in the ZUMA-1 trial were treated with axi-cel. The study completed its primary endpoint of combined overall response rate (ORR) for patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (FL) after 6 months’ follow-up. For all disease types (n = 92), patients treated with axi-cel achieved an ORR of 82% (

 <.0001). After a median follow-up of 8.7 months, 44% of patients responded to axi-cel and 39% of patients achieved a CR. The majority of the population enrolled in the ZUMA-1 trial were patients with DLBCL (n = 77); the ORR and CR rates in this population were 82% and 49%, respectively.

Both axi-cel and tisagenlecleucel are also being evaluated in clinical trials for efficacy and safety for additional indications (Table 1). Results from the ongoing phase I/II ZUMA-3 trial for axi-cel in adults with relapsed/refractory B-cell ALL were reported at the 2017 ASCO Annual Meeting. Among 8 patients evaluable for efficacy, 6 achieved an MRD-negative CR or a CR with partial or incomplete hematopoietic recovery.

Table 1. Ongoing Clinical Trials of CAR T-Cell Therapy in Hematologic Malignancies

The ongoing phase II JULIET trial is investigating the safety and efficacy of tisagenlecleucel treatment in adult patients with relapsed/refractory DLBCL. Preliminary results from JULIET were presented at the 2017 International Conference on Malignant Lymphoma. Of 85 patients who received a single dose of tisagenlecleucel, 51 were evaluable for tisagenlecleucel response with at least 3 months’ follow-up. For these patients, the ORR was 59% (95% CI, 44.2%-72.4%); 43% of patients had a CR, and 16% had a partial remission.

 In October, Novartis filed a supplemental biologics application to expand the indication for tisagenlecleucel based on the JULIET study.

Juno Therapeutics’ CD19-targeted CAR T-cell therapy, JCAR015, was originally expected to secure regulatory approval first. However, the development of JCAR015 was discontinued following 2 clinical holds placed on the phase II ROCKET trial, in which an adverse safety profile revealed an increased incidence of deaths due to cerebral edema.

Despite the disappointing safety concerns with JCAR015, Juno Therapeutics is continuing clinical development of a substantial CAR T-cell therapy pipeline. The ongoing phase I TRANSCEND study is investigating the safety and efficacy of another pipeline CD19-targeted CAR T-cell therapy, JCAR017, and has enrolled patients with relapsed/ refractory B-cell NHL, including DLBCL, PMBCL, FL, and mantle cell lymphoma. Interim data were presented in November 2016 from a total of 28 evaluable patients following treatment with fludarabine, cyclophosphamide, and JCAR017. The majority of the population (n = 25) had DLBCL. Of 20 patients treated with lower-dose JCAR017, the response rate was 80%, with 60% of those patients achieving a CR.

Juno’s experience highlights a complicating factor of clinical implementation of CAR T-cell therapies—the potential for severe, sometimes fatal, treatment-related toxicities. Most prominent are cytokine release syndrome (CRS)&mdash;a severe immune reaction resulting from the release of cytokines from the targeted cancer cells and by immune effector cells recruited to the area&mdash;and neurotoxicity, resulting in brain swelling, altered consciousness, and seizures.

In the ELIANA trial, CRS occurred in 78% of patients, with 27% of grade 4 severity; however, there were no CRS-related deaths. Grade 3 neuropsychiatric events occurred in 15% of patients, but none were grade 4, and there was no incidence of cerebral edema. In the ZUMA-1 trial, adverse events of CRS and neurotoxicity of grade 3 severity or higher occurred in 13% and 28% of patients, respectively; all cases resolved except for a grade 1 memory impairment. The first death from cerebral edema in this trial was recently reported, and although studies will continue as planned, patient consent forms will be amended to reflect the risk.

All CAR T-cell therapies developed to date cause these and other toxicities in at least some patients, but there is substantial variation in the severity and type of toxicity. A prospective registry and a monitoring study were both proposed to assess the long-term safety of tisagenlecleucel for up to 15 years following treatment to gain a better understanding of the toxicity profile and long-term effects of the approved treatment.

Understanding the reasons for these toxicities is a central focus of ongoing research, in addition to the question of long-term safety relating to the risks of using viral vectors and the persistence of CAR T cells in the body after treatment.

The success of CD19-targeted CAR T cells has prompted exploration of other TAAs. Of particular note is the B-cell maturation antigen (BCMA). Until now, CAR T-cell therapies had generated mixed results in multiple myeloma, an incurable B-cell malignancy.

BCMA is a member of the tumor necrosis factor receptor superfamily and is expressed nearly universally on multiple myeloma cells, making it a promising target for CAR T-cell therapy in this tumor type.

Bluebird Bio and the Chinese company Nanjing Legend Biotech are pursuing the development of rival CAR T-cell therapies for the treatment of relapsed/refractory multiple myeloma. Nanjing Legend Biotech’s LCAR-B38M is uniquely engineered, in which the antigen-binding region of the CAR is a non-scFv structure targeting 2 regions of the BCMA antigen. Researchers hope this design will allow for more effective antitumor activity. To address safety concerns, LCAR-B38M is also being administered as 3 smaller infusions rather than a single large infusion.

Both therapies created a buzz at this year’s ASCO Annual Meeting with data suggesting that BCMA-targeted CAR T cells could be a safe and effective way to treat multiple myeloma. Nineteen patients have been treated with LCARB38M, 7 of whom were monitored for more than 6 months. The ORR was 100%; 95% of patients (n = 18) reached near CR without relapse, including 7 patients who achieved CR and were MRD-negative at a median follow-up of 6 months. CRS was observed in 74% of patients but was mostly mild or manageable. Two patients experienced grade 3 or 4 CRS; the patient with grade 4 CRS recovered fully after treatment.12

In Bluebird Bio’s phase I dose escalation trial, bb2121 was administered to 11 patients with relapsed/refractory multiple myeloma in 4 escalating dose cohorts (doses of 5, 15, 45, and 80 x 107 CAR T cells). The ORR in the 6 evaluable patients treated with doses of 15 x 107 CAR T cells and higher was 100%, including stringent CR in 2 patients and MRD-negative responses in 2 patients. There were no reported adverse events of CRS or neurotoxicity of grade 3 or higher, and there were no dose-limiting toxicities.

The unprecedented clinical efficacy of CAR T-cell therapy in patients with hematologic malignancies has not translated into solid tumors to date. However, the safety and efficacy of CAR T-cell therapy for solid tumors, the major cause of cancer-related mortality, have been the focus of a growing number of clinical trials.

Solid tumors are thought to present a number of challenges to the effectiveness of CAR T-cell therapy. These include the difficulty in selecting appropriate target antigens given the substantial heterogeneity even within an individual tumor. CD19 has proved to be such a success story in part because of its near uniform expression on B-cell malignancies, while only present at low levels on normal B cells.

The success of drugs targeting members of the human epidermal growth factor (HER) protein family makes them obvious targets for CAR T-cell therapy in solid tumors, but many other TAAs are also being investigated. Extracellular glycoproteins such as mucin-1, mucin-16, and mesothelin, as well as other cell surface proteins like fibroblast activation protein and L1 cell adhesion molecule, are being explored as targeting moieties (Table 2).

Table 2. Select Ongoing Clinical Trials of CAR T-Cell Therapy in Solid Tumors

Positive data have been demonstrated in trials of HER2-targeted CARs in patients with sarcoma. Findings from a small phase I study were presented at the ASCO meeting. Among 6 patients with refractory or metastatic HER2-positive sarcoma, 1 patient achieved a CR, 2 patients had stable disease, and 3 had progressive disease. The median overall survival in 2 patients who were still alive was 14.2 months.

CARsgen Therapeutics is developing CAR T cells that target glypican-3 (GPC-3), a cell surface protein that is highly expressed in hepatocellular carcinoma (HCC). Phase I clinical trial data, presented at the 2017 ASCO meeting, showed that it was a safe and feasible treatment for Chinese patients with relapsed/refractory GPC-3—positive HCC.

 This study has been terminated for reasons not related to safety, efficacy, or feasibility. A phase II trial in this indication is planned, and a phase I/II trial in pediatric solid tumors is ongoing.

Another unique hurdle to CAR T-cell therapy in solid tumors is the microenvironment, presenting physical, chemical, and biological barriers to CAR T cells, which need traffic to penetrate the tumor site. Many solid tumors are surrounded by a dense stroma and abnormal vasculature that impedes access. The hypoxic, nutrient-deprived, acidic microenvironment is inhospitable for infiltrating T cells. In addition, both the tumor and the microenvironment exert immunosuppressive effects, such as expression of mismatched chemokines, which hinder T-cell migration to the tumor site, and of inhibitory immune checkpoints that switch off infiltrating T cells.

The need to expand the impact of CAR T-cell therapy by addressing the challenges posed by solid tumors, as well as to improve its safety and efficacy, is driving the development of several innovative strategies and next-generation CAR design.

One strategy to overcome TAA heterogeneity in solid tumors is to broaden the specificity of CAR T cells, either by transferring more than 1 population of CAR T cells targeting different antigens or by producing CARs that target multiple TAAs, so-called tandem or bispecific CARs. Several of the latter are currently being evaluated in clinical trials (NCT03097770, NCT03097770, NCT03271515, NCT03271632).

The biopharmaceutical company Endocyte is collaborating with Seattle Children’s Research Institute to develop a novel approach that could create a universal CAR T-cell system capable of targeting any TAA. Their CAR T cells are engineered to bind to small adaptor molecules composed of a fluorescein isothiocyanate (FITC) molecule conjugated to a ligand that targets specific overexpressed receptors on tumor cells.

Instead of the CAR T cells themselves binding to a TAA, an anti-FITC receptor on the surface of the CAR T cell will bind to the FITC end of the adaptor molecule, which allows the activation of the targeted TAA on tumor cells of interest by the free ligand component of the adaptor molecule.

 Several strategies have been developed to address the barriers posed by the tumor microenvironment. Armored CARs and TRUCKs (T cells redirected for universal cytokine killing) are being explored in clinical trials. These are designed to deliver a payload on antigen binding, such as the cytokine interleukin-12 (IL-12), which can help to make the tumor microenvironment more hospitable to immune cells.

In a mouse model of ovarian cancer, IL-12—secreting CAR T cells were found to be more effective and improved survival.

 TRUCKs expressing catalase, to protect T cells from oxidative stress, or heparanase, to improve T-cell penetration through the stroma, are also being explored.

To overcome the ability of tumor cells to suppress the antitumor immune response through exploitation of the immune checkpoint pathways, combinatorial trials of CAR T-cell therapy and immune checkpoint inhibitors are under way. CAR T cells that express antibodies against the PD-1 and cytotoxic T-lymphocyte antigen-4 have also been developed and are in early clinical trials.

 Efforts to make CAR T-cell therapies safer are also under way, in particular seeking out ways to control CAR T-cell activity once the cells have been infused into the patient, to minimize their impact on healthy cells.

One such strategy being explored is to introduce a safety switch into the CAR design, such as suicide genes or inducible apoptotic molecules.24 Another is the development of so-called inhibitory CARs, designed to provide a T-cell inhibitory signal when engaging an antigen on healthy cells.

A particularly exciting research avenue is the application of state-of-the-art genome-editing technologies to the production of CAR T cells. The CRISPR/Cas9 system could be used to create a coveted “off the shelf” CAR T-cell therapy from universal donor cells, which would help to overcome some of the complexities associated with the manufacturing of CAR T cells.

The use of donor T cells is limited by the presence of endogenous TCR and human leukocyte antigens on their surface, which can activate an immune response and result in GVHD. Genome editing is being used to knock out the TCR and HLA genes to bypass these problems, in addition to knocking out genes that can dampen the antitumor immune response, such as PD-1.

The first human trial of CRISPR immunotherapy has been given the green light by the FDA and will evaluate the feasibility and safety of knocking out the PD-1 gene in the T cells of patients with lung cancer (NCT02793856). Another CRISPR study seeking FDA approval will knock out the PD-1 and TCR genes in NY-ESO-1—targeted TCR-engineered T cells.

CRISPR could also be used to improve the delivery of CAR genes. While viral delivery randomly inserts the CAR into the T-cell DNA, CRISPR could more precisely place it in a specific part of the genome. The potential benefit of this approach has been demonstrated in a preclinical study in which CRISPR was used to insert a CAR into the T-cell receptor alpha constant locus, which generated a more uniform expression of the CAR and produced CAR T cells that outperformed traditional ones in mice with ALL.

Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86(24):10024-10028.

Feinberg BA, Fillman J, Simoncini J, Nabhan C. CAR-T cells: the next era in immuno-oncology. Am J of Manag Care. 2017;23(spec no 2):SP48-SP52.

Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017;5:22. doi: 10.1186/s40364-017-0102-y.

Wang Z, Guo Y, Han W. Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. Protein Cell. May 2, 2017. doi: 10.1007/s13238-017-0400-z.

Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370-383. doi: 10.1038/nrclinonc.2016.36.

Buechner J, Grupp SA, Maude SL, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): update to the interim analysis. Presented at: 2017 EHA Congress; June 22-25, 2017, 2017; Madrid, Spain. Abstract S476.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Presented at: AACR Annual Meeting 2017; April 1-5, 2017, 2017; Washington, DC. Abstract CT019.

Shah BD, Wierda WG, Schiller GJ, et al. Updated results from ZUMA-3, a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy, in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL). J Clin Oncol. 2017;35(suppl; abstr 3024).

Schuster SJ, Bishop MR, Tam C, et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)—an interim analysis. Hematol Oncol. 2017;35:27.

Abramson JS, Palomba ML, Gordon LI, Lunning MA, Amason JE, Ferraro-Torres A. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001). J Clin Oncol. 2017;35(suppl; abstr 7513).

FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. BLA 125646: Tisagenlecleucel. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateri- als/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf. July 12, 2017. Accessed September 10, 2017.

Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl; abstr LBA3001).

Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. J Clin Oncol. 2017;35(suppl; abstr 3010).

Holzinger A, Abken H. CARs on the highway: chimeric antigen receptor modified t cells for the adoptive cell therapy of malignant diseases. In: Metodiev K, ed. Immunotherapy - Myths, Reality, Ideas, Future. Incyte; 2017:169-199.

Yu S, Li A, Liu Q, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10(1):78. doi: 10.1186/s13045-017-0444-9.

Yong CSM, Dardalhon V, Devaud C, Taylor N, Darcy PK, Kershaw MH. CAR T-cell therapy of solid tumors. Immunol Cell Biol. 2017;95(4):356-363. doi: 10.1038/icb.2016.128.

Newick K, O’Brien S, Moon E, Albelda SM. CAR t cell therapy for solid tumors. Annu Rev Med. 2017;68:139-152. doi: 10.1146/annurev-med-062315-120245.

Hegde M, DeRenzo CC, Zhang H, et al. Autologous HER2 CAR T cells after lymphodepletion for advanced sarcoma: results from a phase I clinical trial. J Clin Oncol. 2017;35(suppl; abstr 10508).

Zhai B, Shi D, Gao H, et al. A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC). J Clin Oncol. 2017;35(suppl; abstr 3049).

Kim S, Moon EK. Development of novel avenues to overcome challenges facing CAR T cells. Transl Res. 2017;187:22-31. doi: 10.1016/j.trsl.2017.05.009.

Endocyte and Seattle Children’s Research Institute to collaborate on Endocyte’s small molecule drug conjugate bi-specific adaptor molecules for CAR T-cell therapies [press release]. West Lafayette, IN: Endocyte; March 10, 2017. investor.endocyte.com/releasedetail.cfm?ReleaseID=1016917. Accessed September 9, 2017.

Yeku OO, Purdon T, Spriggs DR, Brentjens RJ. Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer. J Clin Oncol. 2017;35(suppl; abstr 3050).

Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15(8):1145-1154. doi: 10.1517/14712598.2015.1046430.

Straathof KC, Pule MA, Yotnda P, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105(11):4247-4254. doi: 10.1182/blood-2014-11-4564.

Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255-2266. doi: 10.1158/1078-0432.CCR-16-1300.

Ren J, Zhao Y. Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9. Protein Cell. April 22, 2017. doi: 10.1007/s13238-017-0410-x.

Rupp LJ, Schumann K, Roybal KT, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. 2017;7(1):737. doi: 10.1038/s41598-017-00462-8.

Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113-117. doi: 10.1038/nature21405.

Chimeric antigen receptor (CAR) T cells have hit prime time, with the 2 recent FDA approvals for this class of cell-based therapy.

Prime Time for CAR T Cells

Checkpoint blockade immunotherapy has been hailed as a significant advance in anticancer treatment. Yet only a subset of patients experience long-term cancer remission as a result of these therapies, because a significant number of those who initially respond eventually develop resistance.

Why do some patients and not others develop resistance? How can primary and acquired resistance to immunotherapy be overcome? These questions are drawing intense interest from the research community. As investigators seek to unravel the mechanisms of acquired resistance, they also hope to shed light on the components of primary resistance.

The biological and genetic processes that may contribute to relapses were a lively area of inquiry during the 32nd Annual Meeting of the Society for Immunotherapy of Cancer (SITC), held November 8-12 in National Harbor, Maryland. Investigators reported findings about a variety of diagnostic tools to monitor immune responses throughout the treatment cycle in preclinical settings, and about the results of explorations into novel therapies and combinations.

"There’s very little so far that we understand about mechanisms of acquired resistance to immune checkpoint inhibitors,” said Katerina Politi, PhD, an associate professor in Yale University’s Department of Pathology and the Yale Cancer Center, in an interview with OncologyLive®.

Since these therapies are a relatively new modality in clinical practice, the prevalence of acquired resistance among patients treated with these agents is unclear. “I’m not sure we know how many patients are affected by acquired resistance,” Politi said. “It might be different for different cancers.”

Politi, who served as a co-chair of a session on immunotherapy resistance at the SITC conference, has used genetically engineered mouse models to study genetic changes in lung cancer that cause resistance to targeted therapies; now, she is exploring cellular changes that may cause or contribute to resistance to immunotherapy.

Politi’s team is studying tumor specimens before treatment is administered and after resistance develops to determine differences at the DNA or RNA level, and in proteins and immune cells. They are using patient-derived tumor xenografts to understand the impact of the alterations they identify. “We want to be able to validate them functionally,” she said.

Antoni Ribas, MD, PhD, a leading authority on immunotherapy and a Giants of Cancer Care® awardwinner, and colleagues have defined 3 types of resistance to immunotherapy that have been manifested in clinical scenarios: (1) primary resistance, in which the cancer fails to respond to therapy; (2) adaptive immune resistance, in which cancer cells are recognized by the immune system but develop ways to protect themselves from attack (may be primary resistance, mixed response, or acquired resistance); and (3) acquired resistance, in which a cancer responds to immunotherapy but progresses after a period of time.

The mechanisms that cause these responses are dynamic; they can evolve in response to environmental and genetic factors and to treatment interventions including surgery, chemotherapy, radiation therapy, and immunotherapy. Notably, they may exist prior to the administration of immunotherapy.

As of November 12, the FDA had approved 6 checkpoint blockade immunotherapy agents: ipilimumab (Yervoy), an anti—CTLA-4 antibody; nivolumab (Opdivo) and pembrolizumab (Keytruda), both anti–PD-1 antibodies; and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all anti–PD-L1 antibodies. These agents were approved based on clinical trials that demonstrated overall or objective response rates ranging from approximately 11% to nearly 70%; in many of the studies, the median duration of response was not reached (Table 1).

able. Checkpoint Immunotherapy Response Rates and Duration in Pivotal Trials

Long-term survival rates for patients with melanoma or non—small cell lung cancer (NSCLC) who were treated with anti–PD-1 inhibitors in early clinical trials exceed what would have been expected with standard therapies in these disease settings. Forty percent of patients with advanced melanoma who started taking pembrolizumab during the clinical trial that led to its initial approval were alive after 3 years, researchers reported at the 2016 American Association of Clinical Oncology Annual Meeting.

The results from the KEYNOTE-001 study showed that 15% of the patients experienced complete remissions according to immune-related criteria (irRC) after taking the PD-1 inhibitor and that nearly 90% of these responders remain in remission. The median overall survival (OS) was 24.2 months.

At the 2017 American Association for Cancer Research Annual Meeting in April, investigators presented updated findings from CA209-003 that they described as the first report of long-term OS rates in patients with metastatic NSCLC treated with an immune checkpoint inhibitor. After Katerina Politi, PhD approximately 5 years of follow-up (minimum follow-up, 58.25 months) the OS rates for patients treated with nivolumab were 42% at 1 year, 24% at 2 years, 18% at 3 years, and 16% at 5 years.

Researchers said those rates were about 4 times higher than the survival that would have been expected with docetaxel.

Nevertheless, acquired resistance has manifested itself in a significant subset. “It is becoming clear that approximately one-fourth to one-third of patients with metastatic melanoma who have objective responses to checkpoint blockade therapy with anti—CTLA-4 or anti–PD-1 will relapse over time, even despite receiving continued therapy,” Ribas and colleagues wrote.

During a presentation at the SITC conference, Valsamo Anagnostou, MD, PhD, included an analysis of progression after response among patients with NSCLC who received checkpoint blockade immunotherapy during 4 clinical trials (Table 2).5 The rates of progression among responders ranged from 19.4% to 48%. Notably, initial response and later progression rates were markedly lower among patients who had received docetaxel, the standard comparator in each trial.

Table 2. Progression Among Responders in Selected NSCLC Trials

Strategies to improve primary response rates and the duration of responses to checkpoint blockage immunotherapies are needed, said Anagnostou, an oncology instructor and researcher at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland. “Despite the clinical benefit, a fraction of patients respond to these therapies and, among the patients who do respond, the majority of them develop acquired resistance. There is therefore an unmet need for understanding mechanisms of response and resistance to these therapies,” she said.

Appropriately selected patients who do not experience tumor shrinkage or regression after initial treatment with an immunotherapy exhibit primary resistance. “In that case, it’s most likely that the cancer is not immunogenic enough to have induced an immune response, so we cannot use its checkpoints to turn it on,” said Ribas, director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center at UCLA, in an interview. Factors intrinsic and extrinsic to the tumor cell have been identified in ongoing studies as contributing to primary and adaptive resistance mechanisms to immunotherapy.

Intrinsic factors include an absence of tumor antigens and genetic factors that prevent immune cell infiltration, while extrinsic factors may be found in the tumor microenvironment; these include myeloid-derived suppressor cells and inhibitory immune checkpoints.1 In acquired resistance, possible mechanisms that have been explored include the loss of T-cell function, lack of T-cell recognition by downregulation of tumor antigen presentation, and development of escape mutation variants in the cancer.1 Ribas and colleagues postulate that each of these mechanism may promote acquired resistance to checkpoint blockade antibodies and to adoptive cell transfer therapies, a category that includes chimeric antigen receptor (CAR) and T-cell receptor therapies.

Researchers are discovering possible overlap of mechanisms of primary and acquired resistance to immunotherapy. “The studies analyzing resistance to immunotherapy identified several genetic alterations that are shared between tumors that are primary resistant and those that acquire resistance under therapy,” said Annette Paschen, MD, an associate professor in the Department of Dermatology at the University Duisburg-Essen and German Cancer Consortium, in an email interview. She also discussed resistance mechanisms at the SITC conference.

One important mechanism of acquired resistance appears to be genomic changes in T-cell receptor clonality that prevent continued recognition of tumor antigens after an initial response, according to research Anagnostou and colleagues conducted at Johns Hopkins.

Investigators analyzed the genomic evolution of 4 patients with NSCLC who had initially responded to anti—PD-1 or anti–PD-1/CTLA-4 therapy and then developed resistance.6 To do so, they performed genome-wide sequencing of protein coding genes and T-cell receptor clonotype analysis on paired tumor specimens, followed by evaluation of eliminated neoantigens in peripheral blood T cells. They also analyzed neoantigens in 1 patient with head and neck squamous cell carcinoma who had been treated with a combination of PD-1 and KIR blockade therapy.

The investigators found that NSCLC tumors that acquired resistance shed between 7 and 18 mutation-associated neoantigens (MANAs) through the elimination of tumor subclones or through the chromosomal loss of truncal alterations.6 Some of the MANAs that were eliminated were in genes that encode peptides recognized by T cells in peripheral blood. This “therapy-induced immune editing of MANAs” appeared to allow the tumor to avoid attack, the investigators wrote, although they noted that larger studies would have to be conducted at various times of relapse and response to confirm these findings.

The focus on neoantigen changes during therapy is consistent with prior studies that have described tumor mutational load as an indicator of response to checkpoint blockade antibodies, Anagnostou noted during her SITC presentation.

“Responses are expected in tumors with a very high mutational load such as mismatch repair— deficient colon cancers as well as in tumors with known environmental exposures such as lung cancer and melanoma, whereas responses are less expected in tumors with a low mutational load such as [pediatric] neuroblastoma,” she said. The next step for the research team was to determine whether changes in the neoantigen landscape could be accurately assessed through circulating cell-free DNA (cfDNA) isolated from the plasma of patients at any stage in the treatment timeline. Investigators used a method called targeted error correction sequencing, or TEC-Seq, that was developed at Johns Hopkins to evaluate sequencing changes in cfDNA.

By comparing cfDNA and TCR dynamics during and after treatment, investigators delineated patterns of response. “For a patient with an ongoing response, there is early clearance of cfDNA [by week 4] and evidence of expansion of TCR clones in the circulation,” said Anagnostou. “For a patient with primary resistance, there is no clearance of cfDNA and no change in productive frequencies.” For patients who initially respond but develop acquired resistance, there is a clearance of cfDNA at the time of response followed by outgrowth at the time of resistance. “There is some expansion of TCR clones at time of response followed by a decrease to pretreatment levels at the time of therapeutic resistance,” said Anagnostou.

She said the findings have implications for the development of immunotherapies that target multiple clonal neoantigens to prevent immune escape. Additionally, she noted that liquid biopsies should be incorporated into the design of future clinical trials.

The evidence thus far suggests that tumors that develop resistance to checkpoint immunotherapy are highly genetically similar to tumor samples taken prior to the development of resistance. A study published in Clinical Cancer Research used genetic and immunologic analysis to study tumor evolution over 5 years in a patient with cutaneous melanoma.

The 60-year-old male patient received anti— PD-1 therapy from the time of metastasis to death; at that time, some metastases were responding to therapy, while others were progressing. Researchers conducted whole-genome sequencing on 26 responsive and nonresponsive tumor specimens (4 premortem, 22 postmortem), but they found few genetic differences.

“At the genomic level, the tumors did not display a significant number of genetic subclones with respect to the cancer cell fraction,” wrote Ascierto and collaborators. “…We found remarkable genetic similarities among regressive/progressing cutaneous metastases, indicating that all were derived from a single subclone that had not diverged significantly.” Investigators concluded that the patient’s disease was driven by a functional loss of NF1, which has been associated in earlier studies with RAS activation in melanoma cells and with MAPK pathway reactivation in resistance to BRAF inhibitors.

Notably, they did not find significant differences in progressing versus regressing metastases either in PD-L1 expression on tumor cells or infiltrating immune cells or in CD8 T-cell densities in intratumoral or peritumoral locations. However, global gene expression profiling revealed distinct gene signatures in progressing and regressing tissue samples. The most differentially expressed gene, LAMA3, a subunit of laminin-5, was also overexpressed at the protein level in progressing metastases. Laminin-5 is associated with epithelial-to-mesenchymal transition and poor prognosis in lung cancer and with the development of aggressive melanoma in culture.

Interruptions in the Interferon-Gamma Pathway

The interferon-gamma (IFNγ) signaling pathway is a critical part of the immune response, and multiple research studies now suggest that defects along the pathway play a key role in immunotherapy resistance. Notably, JAK1/2 mutations, which affect IFNγ signaling, have been found in melanoma samples exhibiting primary resistance, as well as in tumors that developed acquired resistance.

A study published in the New England Journal of Medicine analyzed paired tumor samples of 4 patients with metastatic melanoma who relapsed while receiving pembrolizumab. (The mean time to relapse was 624 days, with a range of 419-888 days). The researchers compared tissue samples from baseline and relapsing lesions through whole-exome sequencing. In the relapse samples of 2 patients, they identified acquired loss-of-function mutations in JAK1 and JAK2, resulting in a lack of response to IFNγ. A truncating mutation in B2M, which encodes the antigen-presenting protein beta-2-microglobulin, was identified in a third patient.

Vol. 18/No. 22 | Oncology Live®

Experts Discuss Ways to Remove Barriers to Optimal Management of CINV

Some Common Oncology Terms Carry Unanticipated Consequences

Cellular Immunotherapy Expert Explains CAR T-Cell Therapy Excitement

Prime Time for CAR T Cells

Immunotherapy Resistance Remains a Puzzle

Most Patients in Need of HCT Can Now Get Transplants