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 the concept of using genetically engineered T cells to fight cancer has been under study for more than 50 years, the most dramatic strides in designing new therapies have come in the past several years.

That is when reports started build- ing about patients with recurrent hematologic malignancies who had experienced long-standing remissions after treatment with chimeric antigen receptor (CAR) T-cell agents directed at CD19. Since then, study results with objective response and complete remission rates of greater than 70% have been disclosed in various lymphoma and leukemia trials.

Given such positive findings, experts feel it is highly likely that the first CARs will reach the US market this year and that more options will be available in the next several years. The FDA currently is reviewing applications for 2 drugs, and pharmaceutical companies have additional compounds in early-phase development.

There are, however, many complex considerations in bringing this new technology to patients, as we explore in our cover story in this issue of 

, “Pivotal Year Looms for CAR T-Cell Therapies.” One of the primary challenges will be identifying and managing the potentially life-threatening adverse events that patients treated with these therapies are at risk of experiencing.

Other challenges will be commercial; for example, the regimens have been designed for the sickest patients in comparatively less common cancers and may be difficult to use in broader populations or earlier in treatment timelines.

Then there is the question of cost both to individual patients and to the healthcare system. Since none of the drugs has reached the market yet, we don’t know the pricing but some analysts said 2 years ago that they expected CAR treatments to cost up to $300,000 per patient.

That brings us to another important point that Editor-in-Chief Maurie Markman, MD, raises in his insightful commentary, “Clinical Trial Reform Is Urgently Needed.” Although we routinely discuss the value of a novel anticancer drug in the context of what it will cost, the real question is how well a therapy works. How we pay for a clinical advance—particularly one as potentially remarkable as CARs&mdash;should be a separate issue.

Our dysfunctional healthcare payment systems have married these concepts. It would be quite a shame for a revolutionary advance such as the CAR agents to be underutilized because of cost concerns. Let’s hope we can figure this out so patients truly bene t from the many years of research that have gone into deliver- ing these therapies.

Articles

CARs Ready to Roll

Platinum and taxane chemotherapies remain standard first-line treatments for epithelial ovarian cancer. The treatment of recurrent ovarian cancer has historically been based on how a patient responded to the first-line regimen. Patients whose cancer recurred 6 months or more after the last platinum infusion are categorized as 

, whereas patients whose cancer recurred within 6 months of the last infusion are classified as 

. Greater understanding of ovarian cancer biology and the emergence of new targeted therapies is diminishing the importance of platinum response in determining how to treat recurrent disease.

 titled “Expert Views on Therapy for Ovarian, Fallopian Tube, and Peritoneal Cancers,” a panel of gynecologic oncology specialists discussed novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions. As panel moderator 

 summarized, “We have had 3 new FDA approvals for targeted therapies in the last 2 years, and I anticipate within the next year, we’ll have 3 more. Our armamentarium is growing, and our paradigms are changing.”

Ovarian cancer, like cancers that affect other organs, comprises many subtypes. Approximately 90% are epithelial, 80% of which are subcategorized as serous carcinomas.

 Serous carcinomas are further divided into high grade and low grade, with high grade accounting for 90% of serous tumors.

 “High-grade serous patients tend to have the worst prognosis compared to those with low-grade serous cancers,” said Angeles 

 She said high-grade serous tumors are further classified according to whether they harbor a homologous recombination deficiency (HRD), such as a germline or somatic 

 gene helps repair DNA and suppresses tumor growth, and current guidelines recommend all women with epithelial ovarian cancer have a blood test for a germline 

alteration. Monk said it surprises him when he meets a new patient who has had epithelial ovarian cancer for a long time but never had a 

 said some experts recommend clinicians also test the tumor for a somatic 

mutation, which a blood test would not detect. 

 reminded everyone that HRD testing is another option. She said although an HRD test does not identify specific somatic mutations, it does indicate whether a patient has an important somatic mutation in the DNA repair pathway.

 said it is important to know whether the “machinery is messed up,” because the cancer cell may have a vulnerability able to be exploited with drugs that induce DNA damage. Secord called the process

 mutation—whether it’s germline or somatic&mdash;or they have another defect that’s causing loss of homologous recombination, then the cells can’t repair themselves once they’re subjected to a DNA-damaging event,” Secord said. Coleman said synthetic lethality explains why patients with high-grade serous ovarian cancers who have a 

 mutation have better outcomes than patients without a

mutation. The same gene that predisposes their cells to malignant transformation makes those malignant cells vulnerable to DNA-damaging drugs.

The poly(ADP-ribose) polymerase (PARP) protein plays a significant role in repairing DNA damage. Monk described how the class of drugs known as PARP inhibitors are designed to block PARP’s enzymatic activity, thereby disrupting DNA repair and causing an accumulation of single-stranded breaks.“If you can’t repair single-stranded breaks, you get a double-stranded break. And if you have a 

-like mutation, you can’t repair the double- stranded break [and] the cell dies,” he said.

The FDA has approved 2 PARP inhibitors for women with ovarian cancer. In 2014, olaparib (Lynparza) received accelerated approval for women with advanced ovarian cancer who have a germline 

 mutation and used at least 3 prior lines of chemotherapy. Approval was based on data from a phase II trial that included 193 heavily pretreated patients with ovarian cancer and a germline 

 The overall response rate (ORR) in this cohort was 31%, and median progression-free survival (PFS) was 7 months.

 Herzog said the most common adverse events (AEs) in the phase II trial were fatigue and anemia. Some patients also experienced gastrointestinal issues, which Herzog said may have been because the formulation of olaparib used in the trial required patients to take 16 capsules per day.

Moore said the phase III SOLO-2 trial, which is meant to be a confirmatory study, uses a new tablet formulation of olaparib. Patients will require fewer tablets than capsules, and Monk speculated the new formula might reduce gastrointestinal toxicity. SOLO-2 recruited women with platinum-sensitive, 

-mutated recurrent ovarian cancer and randomly assigned them to olaparib tablets or placebo. “That study has been reported to be positive in a press release but without any accompanying hazard ratio as of yet, so we’re awaiting data,” Moore said. SOLO-3 is another ongoing trial, which is comparing olaparib with physician’s choice of standard chemotherapy in recurrent ovarian cancer.

 Peer Exchange® panel, Monk accurately predicted that the FDA would soon approve a new PARP inhibitor, rucaparib (Rubraca). On December 19, the FDA granted accelerated approval to rucaparib and to a companion diagnostic test, the FoundationFocus CDxBRCA, which screens ovarian tumor tissue for 

 Rucaparib is indicated for women with advanced ovarian cancer who have received 2 or more lines of chemotherapy and whose tumor harbors a germline or somatic 

Approval was based on findings from 2 single-arm clinical trials (ARIEL2 and Study 10), which included women with 

-mutated advanced ovarian cancer. “They particularly were interested in looking at those patients who had a germline or a somatic 

 mutation and had received greater than 2 lines of prior chemotherapy,” Moore said. At the 2016 European Society for Medical Oncology Congress, Rebecca Kristeleit, PhD, presented a pooled efficacy analysis for 106 women in the studies, which showed an investigator ORR of 53.8% and a median PFS of 9.2 months.

 Moore praised the remarkable outcomes and the safety profile; she said most AEs observed in the studies were common class effects of PARP inhibitors.

Coleman and his colleagues recently published additional findings from ARIEL2, which showed rucaparib was more effective in patients with a

 mutation who had a high degree of genomic loss of heterozygosity (LOH), or what Coleman called“genomic scarring.”

 Coleman said, “Rather than going through and trying to pick off which genes are actually the vulnerable ones...it was just easier to look across all of the genes.”

Table. Progression-Free Survival for Niraparib Versus Placebo in the NOVA Ovarian Cancer Trial

Niraparib is another PARP inhibitor the panel predicted was likely to earn FDA approval. Niraparib was evaluated in the phase III NOVA trial (n = 553) as maintenance therapy for women with platinum-sensitive, recurrent ovarian cancer.6 The authors stratified the women into 3 cohorts: those with a germline 

 mutation, those without one, and those without one who were HRD positive. “The maintenance niraparib approach resulted in improved PFS in all 3 groups,” Secord said (Table). She added that when she first learned of the results, she assumed patients with a somatic tumor mutation accounted for the positive results in the niraparib cohort of women with no germ- line mutation. She was pleasantly surprised to find niraparib also benefited women who carried neither a germline nor a somatic 

“I’m still confused about this maintenance idea,” Monk said. “In the NOVA trial, maintenance is in the title, but half the patients still have cancer. How can I call that maintenance if they had partial responses until their last treatment?” The experts agreed the terminology was imperfect, and Herzog suggested the NOVA trial was more like a switch study.

Veliparib is a fourth PARP inhibitor, which is being evaluated in an ongoing phase 3 trial as an addition to standard frontline chemotherapy for ovarian cancer and as maintenance therapy after chemotherapy. “Myelosuppression becomes a very real issue with DNA-damaging chemotherapy, but veliparib is probably less potent [than the other PARP inhibitors] on that specific angle,” Coleman said.

No trials have compared the PARP inhibitors head- to-head for ovarian cancer, and the panel agreed on the need for caution when making cross-trial comparisons. “You need to be aware of what the methodology was—it’s very important,” Herzog said. He suggested clinicians look at the toxicities observed with each PARP inhibitor and the labels once they are all approved.

“There are some differences between these drugs and how they bind to the different PARP receptors,” Secord said. She pointed out that niraparib is associated with a higher risk of thrombocytopenia than other PARP inhibitors. Herzog noted that the PARP inhibitors also have differences in bioavailability.

Moore said it was too early to know whether one PARP inhibitor was better than another. “Certainly they have differences in the Petri dish in terms of potency, but even the 3 we’re talking about are all pretty potent PARP inhibitors, and they all work in the studies that they have been tested in,” she said.

Ongoing trials of the various PARP inhibitors should provide more data to guide clinicians’ choices once they are all available for use in practice. Some studies are assessing outcomes by HRD score, others are assessing PARP inhibitors as frontline therapy or in combination with other classes of agents, such as VEGF inhibitors. Herzog predicted future trials would likely combine them with immune checkpoint inhibitors and other immunotherapies. The panelists expressed excitement about the many new options available for their patients. “We’ve had a real change—a paradigm shift,” Herzog said.

The group agreed that despite the advances, many challenges remain, such as drug resistance. Herzog said he expects the recent evolution in clinical trial design will lead to data-driven answers to critical questions, such as how to sequence PARP inhibitors with other agents or which combinations work best for which patients. “We have a light at the end of the tunnel,” Coleman concluded.

Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline 

 2015;33(3):244-250. doi:10.1200/JCO.2014.56.2728.

US Food and Drug Administration. FDA grants accelerated approval to new treatment for advanced ovarian cancer [press release]. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm533873.htm. Published December 19, 2016. Accessed January 16, 2017.

Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC) and a 

 mutation (BRCAmut); analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). 

Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 

 2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9.

Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 

A panel of gynecologic oncology specialists discusses novel agents for the second, third, fourth, and even fifth lines of therapy and the growing importance of molecular signature, histology, and time to recurrence in treatment decisions.

PARP Inhibitors Are Changing Paradigm in Recurrent Ovarian Cancer

Chimeric antigen receptor (CAR) T-cell therapies have already produced clinical trial results that—even by the lofty standards set by emerging immunotherapies&mdash;have been stunning. This year should demonstrate whether the most tested treatments in the class perform as well in real-world patients and whether new agents can produce similarly spectacular trial results against a wider variety of cancers.

Kite Pharma has initiated a rolling submission with the FDA for permission to market KTE-C19 (axicabtagene ciloleucel) for use in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.

 The new drug application will rest largely on the strength of the ZUMA-1 trial, which produced an objective response rate (ORR) of 91% and a complete remission (CR) rate of 73%.

Novartis, meanwhile, plans to seek FDA approval early this year to market CTL019 (tisagenlecleucel- T) to pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

 That application will hinge on the positive results of the phase II ELIANA trial, which, according to an oral presentation at the 2016 American Society of Hematology (ASH) Annual Meeting, produced a CR or a CR with incomplete blood count recovery (CRi) in 82% (41 of 50) patients with B-cell ALL.

The FDA awarded breakthrough therapy designations to both medications on grounds that they address unmet needs.

 The agency also is evaluating two CAR T-cell therapies from Juno Therapeutics, JCAR017 and JCAR015, through the breakthrough therapy program, which is aimed at prioritizing reviews of promising drugs.

Development plans for JCAR015 in adult patients with relapsed/refractor B-cell ALL have been in flux since November 2016 when Juno Therapeutics voluntarily placed the phase II ROCKET trial on hold after 2 patients, like 3 other participants before them, died from cerebral edema.

 The hold does not affect the company’s efforts to develop JCAR017 or other CAR T-cell therapies.

Other companies seeking to bring CAR therapies to market include:

• Bluebird Bio is working with Celgene to conduct a phase I trial of its lead CAR T candidate, bb2121, in patients with relapsed and refractory multiple myeloma.6 It also reports several other T-cell receptor (TCR) adoptive immunotherapy candidates in preclinical stages of development.

• Cellectis has begun phase I trials of its lead therapy, UCART19, in patients with ALL and chronic lymphocytic leukemia (CLL)

 and has asked the FDA for permission to launch phase I trials of UCART123 in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm.

• Adaptimmune and partner GlaxoSmithKline are conducting early-stage trials of NY-ESO TCR in patients with synovial sarcoma, multiple myeloma, melanoma, ovarian cancer and non— small cell lung cancer (NSCLC). The company has also launched a phase I trial of MAGE-A10 TCR in NSCLC and is about to begin testing the treatment against melanoma as well as cancers of the bladder, head and neck.

If these novel CAR therapies prove successful, the treatments could provide extra years of life for real-world patients. That would be great news for patients, particularly those with recurrent and incurable hematological cancers, which are the current focus of most companies.

“There is definitely reason for optimism that CAR-T treatments will prove effective against a wide range of hematological cancers. There are a number of B-cell malignancies that express the CD19 antigen that it targeted in most of the treatments that have done so well in trials to date, and we’re starting to see some evidence that CAR-T therapies with alternate targets or alternate vectors may work against a number of CD19- negative malignancies,” said Charles Mullighan, MD, chairman of ASH’s Committee on Scientific Affairs.

“Of course, it will be several years until we know for sure how big an impact CAR-T will have on hematology as a whole, but we are already seeing this as a major new weapon in our arsenal against relapsed or refractory ALL,” he said. Meanwhile, efforts to engineer CAR T-cell therapies for use against solid tumors continue. New targets for CAR therapies in solid tumors and a greater understanding of the differences in their activity compared with hematologic malignancies is needed, researchers have said.

, gene engineering pioneer Carl H. June, MD, a Giants of Cancer Care® award winner, and colleague Laura A. Johnson, PhD, both of the University of Pennsylvania’s Perelman School of Medicine, noted that the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat metastatic melanoma helps set the stage for the use of adoptive cell therapy in solid tumors.

Although there has been a lack of success with CARs in solid tumors thus far, there also have been few completed clinical trials with published data, the authors said.

Steven A. Rosenberg, MD, PhD, a groundbreaking immunotherapy researcher who has helped develop the new generation of CARs, also acknowledged the success of CAR therapies thus far and the knowledge gap that must be overcome to extend their use into solid tumors.

“CAR T-cell therapies have produced very impressive results in a number of trials. I believe they will be able to extend the life and possibly cure relapsed or refractory lymphoma and leukemia patients whose cancers can be targeted by CARs,” said Rosenberg, chief of the National Cancer Institute’s Surgery Branch, who also has been named a Giants of Cancer Care

“Unfortunately, it appears at this point that CAR T cells will not work against the vast majority of solid tumor types that together account for the vast majority of cancer deaths. CAR T-cell therapy is a revolutionary treatment, but only for a relatively small number of people. I believe an important part of the future of cell transfer therapy for cancer will involve natural T cells reactive with mutations expressed by the cancer,” said Rosenberg.

The idea of grafting CARs onto T cells drawn from individual patients so that those T cells would attack particular diseases with those particular antigens dates back more than 3 decades. A team led by Zelig Eshhar, PhD, an immunologist from the Weizmann Institute of Science, produced the first functional CAR T cells in 1989,

 but early efforts to direct CAR T cells against cancer proved disappointing.

That gave way to cautious optimism and then considerable excitement, however, when investigators began testing second-generation therapies with CARs that target the B-lymphocyte antigen CD19, which is frequently expressed in many hematological cancers.

Initial trials of such agents against NHL demonstrated far better persistence although limited efficacy.

 These results led to the more recent trials against B-cell lymphomas and ALL that have made headlines around the world.

CAR T-cell therapy typically begins by bringing the patient in for several hours of leukapheresis, a process in which the patient’s blood is drawn, the T cells are removed, and the remaining serum is returned to the patient. The T cells are sent to a laboratory, where the CARs are grafted on; the resultant CAR T cells are reproduced many times over before being injected back into the patient.

The most common adverse events (AEs) arising from the current generation of CAR T therapies are cytokine release syndrome (CRS), neurologic toxicity, and Bcell aplasia.

 Severe side effects requiring lengthy hospital stays are common. Such reactions make CAR T-cell treatments punishing even by the standards of cancer care, but trials persist because some treatments have produced remarkable results for patients with no other effective options.

 for example, all had aggressive refractory B-cell lymphoma. In the second of the 2 cohorts in the trial (n = 20), 36% of participants had received ≥5 prior therapies, 82% were refractory to their second-line

therapy, and 18% had relapsed on stem cell transplant. Yet this group of patients who achieved a 73% CR rate after receiving KTE-C19.

Grade ≥3 adverse events (AEs) were experienced by 91% of patients in cohort 2, and 73% of participants had serious AEs. A single episode of cardiac arrest was the only grade 5 event. CRSspecific symptoms, which were all grade 1/2, included pyrexia (82%), hypotension (27%), tachycardia (27%), and other events (18%). To treat CRS, 45% of patients received tocilizumab and 36% were treated with steroids, which resolved CRS for 9 of 10 patients.

These results generated much excitement at the 2016 ASH Annual Meeting, as did findings reported from the ELIANA trial.

 The primary analysis for the first 50 patients enrolled in the ELIANA trial indicated that the CR rate was 68% and the CRi rate was 14%. All patients with a CR/ CRi also tested negative for minimal residual disease (95% CI, 69-91; 

 <.0001). The 6-month overall survival rate was 89% (95% CI, 76-95) and the disease-free survival rate was 60%.

These patients also were heavily pretreated. More than half (56%) had received a prior stem cell transplant, and the median number of prior lines of therapy was 3 (range, 1-8). Patients had primary refractory (10%), chemorefractory (11%), and relapsed ALL (79%).

In terms of AEs, 79% experienced CRS, of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1-22) and lasted for a median of 8 days (range, 1-36). Fifty-nine percent of patients with CRS were admitted to the intensive care unit for a median of 8 days (range, 1-34).

To resolve CRS, patients required treatment with anti-cytokine therapy (51%), high dose vasopressors (33%), invasive ventilation (20%), and dialysis (12%).

Meanwhile, Juno is reporting strong results from several of its CAR T-cell therapies in development. The company and its partners have continued a trial of JCAR014 against CLL, a trial of JCAR018 against CD19-negative ALL, and trials of JCAR017 against pediatric ALL and NHL. The most recent results for JCAR014 against CLL come from a phase I study of heavily pretreated patients who had failed on ibrutinib. Follow-up tests showed that 4 of 19 patients evaluated for efficacy after JCAR014 and fludarabine/cyclophosphamide had a CR and 10 of 19 patients had a partial response.

In the phase I TRANSCEND trial, JCAR017 demonstrated a 60% complete response rate in patients with relapsed or refractory CD19-positive NHL. 

 The study administered JCAR017 at various doses to patients with diffuse large B-cell lymphoma, grade 3b follicular lymphoma, and mantle cell lymphoma. The ORR with the lowest dose of the therapy was 80%. CRs were seen in patients with double- and triple-hit lymphoma and for 1 patient with CNS disease.

There were fewer AEs seen with JCAR017 compared with other CD19-targeted CAR T-cell therapies. None of the enrolled patients experienced severe CRS. Thirty-six percent of patients had grade 1/2 CRS and just 1 participant required treatment with tocilizumab. Additionally, 5 patients (14%) had severe neurotoxicity, all of which resolved with treatment.

As CAR T-cell therapies move toward FDA approvals, questions have arisen about whether the cost of the revolutionary new treatments will be a limiting factor. No CAR T-cell therapy has reached the market, so discussion about what pharmaceutical companies will charge for such treatments is necessarily speculative but financial analysts tend to estimate that the price will be several hundred thousand dollars.

Part of this pricing stems from factors common to all new drugs, such as the high cost of trials, but much of it reflects the high cost of making a custom treatment from the individual T cells of each patient. Drugmakers continue to improve their manufacturing processes, so there’s hope that a combination of increasing competition and efficiency could drive down initially high treatment costs.

There is also hope that technology from Cellectis will allow for the mass production of “off-the-shelf” CAR T-cell therapies that begin with stem cells rather than individual patient donations. Indeed, this approach has drawn interest from Pfizer and other companies looking for a fast way to enter the market for CAR T-cell treatments.

Cai Xuan, PhD, an analyst who covers oncology and hematology for GlobalData, sees price as a potential barrier to widespread adoption of CAR T-cell therapy in the near term. “At present, even if you ignore all the questions about whether CAR T will have any real use against solid tumors, it’s hard to see how it would become a common treatment against the 43,000 or so hematological cancers diagnosed in the US each year,” said Xuan. “The only way it would replace transplant therapy as the standard of care for many of these cancers would be a head-to-head trial, which is not in the works right now and would be very expensive to conduct,” she said. “If the idea was to use CAR T in conjunction with transplant therapy to increase the cure rate, that could meet a lot of resistance from a reimbursement perspective.

Adding another half-million dollars to the cost of transplants that already cost $250,000 to $300,000 and are curative in some cases—the outcomes for that would have to be much better than doing the transplant alone to justify the cost. “That’s not to say CAR T definitely won’t turn out to be a widely applicable breakthrough at some point, but the evidence just isn’t there yet,” Xuan added.

Kite Pharma initiates rolling submission of U.S. Biologics License Application (BLA) for KTE-C19, its Investigational anti-CD19 CAR-T therapy, for the treatment of patients with relapsed/ refractory aggressive B-cell non-Hodgkin lymphoma (NHL) [press release]. Santa Monica, CA: Kite Pharma, Inc; December 4, 2016. http://ir.kitepharma.com/releasedetail.cfm?Release- ID=1002522.

Locke FL, Neelapu SS, Bartlett NL, et al. A phase 2 multicenter trial of KTE-C19 (anti-CD19 CAR T Cells) in patients with chemorefractory primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results From ZUMA-1. Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 998.

Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL[press release]. Basel, Switzerland: Novartis; December 4, 2016. https:// www.novartis.com/news/media-releases/novartis-presents-results- first-global-registration-trial-ctl019-pediatric-and Breakthrough therapies.

Friends of Cancer Research. www.focr. org/breakthrough-therapies?title=&field_sponsor_value=&- field_year_value%5B%5D=5. Accessed February 10, 2017.

Juno Therapeutics places JCAR015 phase II ROCKET trial on clinical hold [news release]. Seattle, WA: Juno Therapeutics, Inc; November 23, 2016. http://ir.junotherapeutics.com/phoenix. zhtml?c=253828&p=irol-newsArticle&ID=2225491.

bluebird bio announces interim phase 1 dose escalation data for its anti-BCMA CAR T product candidate in patients with relapsed/ refractory multiple myeloma [news release]. Cambridge, MA: bluebird bio, Inc; November 30, 2016. http://investor. bluebirdbio.com/phoenix.zhtml?c=251820&p=irol-newsArticle& ID=2226688.

Our focus: integrated product platforms with broad therapeutic potential. bluebird bio, Inc. https://www.bluebirdbio.com/ our-focus/. Accessed February 7, 2017. Cellectis announces first patient treated in phase 1 trial of UCART19 in pediatric acute B lymphoblastic leukemia (B-ALL) [news release]. New York, NY: Cellectis; June 20, 2016. http://www.cellectis.com/en/content/cellectis-announces- first-patient-treated-phase-1-trial-ucart19-pediatric- acute-b-1.

Cellectis submits IND application for UCART123, an allogeneic gene edited CAR T-cell product candidate, in AML and BPDCN [news release]. New York, NY:

Cellectis; January 3, 2017. http:// www.cellectis.com/en/content/cellectis-submits-ind-application- ucart123-allogeneic-gene-edited-car-t-cell-product-1.

From the promise of immunotherapy, a pipeline of opportunity. Adaptimmune. http://www.adaptimmune.com/pipeline/pipeline- overview. Accessed February 7, 2017.

Johnson LA, June CH. Driving gene-engineered T cell immunotherapy of cancer.

. 2017;27(1):38-58. doi:10.1038/ cr.2016.154.

Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. 

. 2006;12(20 pt 1):6106-6115. doi:10.1158/1078-0432.CCR-06-1183.

Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor—modified T cells in lymphoma patients. 

 2011;121(5):1822- 1826. doi:10.1172/JCI46110.

Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. 

. 2016;127(26):3321-3330. doi:10.1182/blood-2016-04-703751.

Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.

Abramson JS, Palomba L, Gordon LI, et al. Transcend NHL 001: Immunotherapy with the CD19-Directed CAR T-Cell Product JCAR017 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 4192.

Ward A, Crow D. Race to control costs of cancer therapy revolution. Financial Times. www.ft.com/content/ad76a316- 9cee-11e5-b45d-4812f209f861. Published December 7, 2015. Accessed February 7, 2017.

Chimeric antigen receptor T-cell therapies have already produced clinical trial results that, even by the lofty standards set by emerging immunotherapies, have been stunning.

Pivotal Year Looms for CAR T-Cell Therapies

Oncology and hematology arguably attracts more research funding, more media attention, and more talented minds than any other medical specialty—but that wasn’t always the case. When Robert J. Mayer, MD, graduated from Harvard Medical School in 1969, the profession was just emerging from its infancy. Its training programs were still a work-in-progress, and it struggled to attract top researchers.

Thousands of people deserve some of the credit for changing that reality, but Mayer deserves a particularly significant share. He has, like all Giants of Cancer Care

, published important papers. Indeed, Mayer’s research has helped create standards of care for leukemias and gastrointestinal cancers.

Perhaps more importantly, though, Mayer has spent much of his career working to improve and expand the entire field of oncology and hematology. He was a key architect of one of the first postgraduate training programs in cancer, a tireless worker for the development of professional groups such as the American Society of Clinical Oncology (ASCO), a catalyst for the increased specialization among cancer doctors, and a mentor to hundreds of young physicians from institutions all around the world. He was, in other words, a driving force in the professionalization of an entire specialty.

“Bob has a commitment, not only to cancer patients and cancer research, but to the field of oncology itself. He is just one of life’s natural mentors, and he has mentored individuals at his own and at other institutions,” said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco.

“I first met him when a flight cancellation stranded us both at Frankfurt Airport on the way back from a conference where I’d done a small presentation. He was already well known and I was just a very junior researcher. He introduced himself and we spent the day looking for a way home while we talked about my research and my interests.

Within a week of returning to San Francisco, he had appointed me to a committee. He basically mentored me from across the country. He gave me the opportunity to do truly meaningful work far faster than I could have done otherwise, and he has done the same for a number of accomplished researchers.”

Mayer’s commitment to mentoring may stem from the difference between his years as a college undergraduate and his years as a medical student. During the former, Mayer developed a deep and lasting relationship with a faculty adviser who helped him make the most of his time inside and outside the classroom. During the latter, Mayer’s adviser left a few months into his first year, and the school did not replace him. Mayer overcame that challenge, but he had always been unusually bright and energetic. Born to Jewish immigrants who fled Nazi Germany for Long Island in the late 1930s, Mayer decided at an early age to follow in his father’s footsteps and become a doctor. He graduated first in his high school class and went on to be a standout undergraduate at Williams College before moving on to Harvard Medical School and a residency at Mount Sinai Hospital in New York. He then took a fellowship at the National Cancer Institute (NCI), both because it was then the world’s leading center of cancer research and because the job fulfilled military obligations that might otherwise have sent him to Vietnam.

Mayer says he learned more about medicine in a few years at the NCI than he did in all his prior medical training. He was soon, however, on his way back to Boston, when Emil Frei III, MD, offered him a job at a new cancer center that Harvard was building. It was only a 1-year fellowship, but Mayer so enjoyed working at what would come to be known as the Dana-Farber Cancer Institute that he has stayed for an extra 40 years (and counting).

“The NCI was a wonderful place to treat patients and do research, but it had no ties to any medical school and it trained no residents, so it was really missing most of the teaching component that had been integral to academic medicine for more than a century,” Mayer said.

“What’s more, virtually none of the academic centers with medical schools and residency plans had programs focused on oncology and that’s what Dr Frei wanted to create at Harvard and Farber. I believed it was vitally important to teach doctors far more about cancer than they were learning, so I very much wanted to be a part of that effort.”

It is hard to imagine now how quickly the field of cancer medicine has grown over the past several decades. Another Giants of Cancer Care® winner, Emil J. Freireich, MD, DSc, recalled that as late as the 1940s, the entire medical school curriculum on systemic cancer could be boiled down to a few sentences: there is no treatment; just keep your patients comfortable. In addition, less than 20 years elapsed between Sidney Farber’s discovery of the first antifolate treatment in the late 1940s and the first treatment that could cure some cases of acute lymphoblastic leukemia (ALL). Less than 30 years elapsed between Farber’s breakthrough experiment and the development of a broad spectrum of treatments for many more malignancies.

By the time Mayer returned to Boston in 1974, millions of patients who would have quickly died from their disease in years past were demanding newly developed forms of effective cancer treatment, but virtually no doctors were trained to provide them. What’s more, the Nixon administration was pouring billions of dollars into cancer research (back when $1 billion was worth more than 5 times as much as it is today), yet there were hardly any researchers who had enough experience in cancer biology to use the money wisely. Mayer launched a medical oncology fellowship program in 1975 that brought advanced cancer training not only to Dana-Farber, but also to Brigham and Women’s Hospital and Massachusetts General Hospital. He also helped design the first oncology and hematology curriculum at Harvard Medical School and define the hematology and oncology rotations for residents at all of Harvard’s hospitals.

As he was doing this, Mayer was also active in supporting ASCO, the professional organization of cancer specialists. He has, in the past 40 years, held every conceivable position at ASCO. He has recruited members, shaped its system for adopting standards of care, designed educational programs for members, and raised millions of dollars. He has even headed the entire organization. In 1974, when Mayer attended his first ASCO meeting, there were only 250 members in attendance. They could all go out for a drink together in a single large bar. Today, ASCO has more than 35,000 members, and colleagues say Mayer deserves as much credit as anyone, both for the organization’s growth and for its success in disseminating best practices.

Colleagues also say that Mayer deserves praise for his skills as a clinician. “Any discussion of career achievements tends to get focused, with some justification, on things that affect large numbers of people: breakthroughs made, protégés trained, organizations built. They often don’t mention whether a great doctor was actually a great doctor, but any piece on Bob should mention that he is truly great at treating individual patients, as good as any clinician I have seen,” said George P. Canellos, MD, who ran Dana-Farber’s Division of Medical Oncology from 1975 to 1995.

“My mother-in-law had a serious blood disorder. She went to see another doctor, who was probably better than average, but he still wasn’t equipped to make a plan for managing such a complex disorder and to communicate the plan to her. She was depressed. She was confused. She was giving up hope. I told her to go see Bob, and the next time I saw her, she seemed like a new woman. She understood her situation and the plan for treating it. She was even optimistic. I asked her what had happened during her visit with Bob and she said, ‘It was like being in a downpour and having someone open an umbrella over my head.’ That’s the best description I’ve ever heard of a great clinician, and that is exactly the sort of impact Bob has on a lot of patients.”

 Mayer’s commitment to education, clinical care, learned societies and other interests, which range from being the associate dean for admissions at Harvard Medical School to serving as a trustee for the Boston Symphony, have not prevented him from doing significant research. To the contrary, he has spent the past 45 years publishing papers that at first ranged from basic research to trial results in both leukemia and gastrointestinal cancer and then—after Mayer decided that an increasing knowledge base demanded greater specialization&mdash; focused exclusively on gastrointestinal cancers. There are many who believe that Mayer’s very public decision to specialize persuaded many other academic physicians to do likewise and, as a result, brought increased research and treatment expertise to every tumor type.

The best known of Mayer’s papers tend to be those that report on trials of new drugs and new treatment protocols. In 1994, for example, he led a group that demonstrated the efficacy of the high-dose cytarabine (HiDAC) regimen for some patients with acute myeloid leukemia (AML); that treatment is still used today in many patients who have AML. In the years since then, Mayer has conducted trials that have determined optimal postsurgical treatment for patients with cancers of the colon and rectum. He also led a recent research effort that demonstrated the effectiveness of a novel drug, TAS-102, in the treatment of refractory colorectal cancer.

Looking forward, Mayer sees a wide range of interesting research topics. He is, like nearly everyone else in the cancer world, excited about the incredible results seen with drugs that modulate the immune system, and he is interested in developing better ways to determine, in advance, which patients will respond. Indeed, much of his focus these days is on learning useful ways to differentiate gastrointestinal cancers and finding which treatments work with specific tumor subtypes.

That said, such research efforts will not crowd out his other activities.

“There are times when I think that I have spread myself too thin over the course of my career, that I might have accomplished more if I had concentrated my efforts on just a couple of fundamental activities. Most of the time, however, I feel that the variety has kept me from burning out and that each thing I do makes me better at the others. Working with patients makes me a better researcher. Doing research and editing journals keeps me up-to-date with what students need to know and how I should treat patients,” Mayer said. “There are certainly benefits that come with specialization, but there are also benefits that come with living a well-balanced life.”

Robert J. Mayer, MD, who helped the field of oncology develop while conducting groundbreaking research, was honored in the Gastrointestinal Cancer category with a 2015 Giants of Cancer Care® award, a program that OncLive developed to recognize leaders in the field.

A Master Mentor Who Nurtured a Field

A wide-ranging clinical trial is investigating a novel method of determining treatment regimens for acute myeloid leukemia (AML) based on genomic testing for each individual patient. The Beat AML Master Trial will assess up to 10 biomarker-based therapies simultaneously for patients with newly diagnosed AML.

“Rather than taking all AML patients over the age of 60 and treating them the same way, the study takes into account their cytogenetics and their mutational status, and assigns them to a rational therapy based on that,” said John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research and a distinguished professor of medicine at Ohio State University, and chief medical officer for the Beat AML subdivision of the Leukemia and Lymphoma Society (LLS). LLS is leading the trial.

One of the main goals of the phase Ib/II trial, which is expected to last 2 years, is to find alternative treatments to chemotherapy. “With chemotherapy given with AML, there’s about a 10% mortality at 30 days, and it’s a very rough therapy, which is what we’re trying to get away from,” Byrd said.

Beat AML is open to newly diagnosed patients 60 years and older who have AML, do not have signs of leukostasis requiring urgent therapy, and do not have symptomatic central nervous system involvement (NCT03013998).

Although Beat AML may include as many as 10 experimental arms over the course of its development, it is starting with 4 novel therapies:

—The monoclonal antibody blocks CD200, an immune checkpoint expressed on AML cells. The drug has been tested in trials for chronic lymphocytic leukemia (CLL) but has not yet been evaluated in AML or solid tumors, according to Byrd. Patients who test negative for core binding factors (AML with t[8;21] or inv[16] mutations) or who test negative for the study biomarkers will be eligible for samalizumab in combination with induction therapy, followed by samalizumab maintenance therapy, during the phase I portion of the study. Only core binding factor patients will be enrolled during the phase II portion of the study.

—This small molecule will be administered to patients with IDH2-mutated AML. Patients will receive up to 5 cycles of enasidenib; those who respond or achieve stable disease can stay on the treatment while those who progress will be given the hypomethylating agent azacitidine.

—Patients with MLL translocation will be eligible for entospletinib, a SYK inhibitor that targets B-cell signaling. Patients with the mutation will receive entospletinib for a month; if they respond, they can continue taking the drug while those who do not respond move on to azacitidine.

—Participants with CD33-positive AML will receive BI 836858 plus azacitidine, followed by that combination as maintenance therapy. The drug is a monoclonal antibody with an engineered Fc-gamma receptor.

Overall, an estimated 500 patients are expected to participate in the trial. Each arm will have 25 to 50 patients, with the expectation that participants move from one therapy to another if benefit from the treatment is not apparent. “If we see significant benefit in the 25 [patients], enough to build a body of clinical data that is respectful and the duration of remission is extended, the arm could serve for potential marketing approval,” Byrd said.

In terms of adverse events (AEs), the regimens being studied have shown favorable tolerability, particularly when compared with traditional AML therapy, Byrd said. With immunotherapy drugs, the most commonly observed AEs have been infusion- related or cytopenia, although these events can be hard to differentiate from the symptoms of AML itself. With samalizumab, rash is typically seen but the drug is otherwise well tolerated, Byrd said.

Entospletinib sometimes affects liver tests, so investigators for that arm of the study will monitor patients for liver function impairments, Byrd said. Other AEs include rash and diarrhea, but are low-grade. For enasidenib, the most frequent toxicity is differentiation syndrome, where patients can develop pleural effusions and shortness of breath, and some individuals will experience an AML tumor flare before improving.

A key goal of the study will be to evaluate the logistical process employed. “The endpoint of the master study is to see if we can feasibly do this: to assign patients to receive treatment within 7 calendar days of the samples arriving at the laboratory and to be sure that there’s not any adverse events associated with that,” Byrd said.

Other endpoints include clinical response rate, which consists of complete and partial responses, and toxicity, minimal residual disease status, and quality-of-life impact. For regimens that have shown higher response rates than traditional therapy, the endpoint would be overall survival at 1 or 3 years that matches what is achieved with chemotherapy, Byrd explained. “The study is designed to adapt quickly to results we see, so a lot of the studies will be done in relatively real time so that we can learn, and we are very adaptive to the knowledge we store,” he said.

If this novel strategy works, it could change the standard of care in that patients with AML would receive therapy based on genomic profiling rather than undergo the same treatments, said Byrd. LLS contends that the standard of care for patients with AML has not changed in 40 years.

The Beat AML trial is launching initially at 5 leading cancer centers: The Ohio State University Comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center, OHSU Knight Cancer Institute, Dana-Farber Cancer Institute, and Massachusetts General Hospital Cancer Center. Pharmaceutical developers participating in the trial thus far are Alexion (samalizumab), Boehringer Ingelheim (BI 836858), Celgene (entospletinib), and Gilead Sciences (enasidenib). Foundation Medicine and Genoptix are providing genomic assays.

A wide-ranging clinical trial is investigating a novel method of determining treatment regimens for acute myeloid leukemia based on genomic testing for each individual patient.

Biomarker-Driven Study Aims for Genomic Breakthroughs in AML

Pancreatic cancer, the fourth-leading cause of cancer death in the United States, has a 5-year survival rate of less than 7%. Pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, is usually diagnosed after the cancer has reached an advanced stage. The only cure is to catch the disease early. As a result, only a minority survive, with most patients dying within a year of diagnosis. There is an urgent need for novel therapeutic approaches.

My laboratory is taking an approach that focuses on the unique metabolic adaptations of this tumor. One area of study involves the incredible metabolic flexibility that enables pancreatic tumor cells to fuel their growth. Pancreatic tumor cells are metabolic scavengers. When oxygen and glucose, normally supplied by the bloodstream, are in short supply, pancreatic tumor cells can produce needed metabolic substrates through a self-digestion process called autophagy.

During autophagy, damaged cell parts are enveloped into vesicles, which fuse with lysosomes. These pockets in turn break down proteins and fats into metabolites, which are recycled to build new DNA strands and membranes that support uncontrolled cell growth of these cancers. We have shown that inhibition of autophagy inhibits the growth of pancreatic cancer cells in culture and in mouse models.

We have recently identified a new kind of metabolic crosstalk between pancreatic tumor cells and pancreatic stellate cells, which also is related to metabolic flexibility. We found that pancreatic tumor cells signal stellate cells to secrete the amino acid alanine. Stellate cells degrade proteins through autophagy, releasing alanine, which in turn is taken up by the tumor cells and used as fuel instead of glucose. Inhibition of autophagy in the stellate cells disrupts this metabolic crosstalk and impairs the growth tumors. Clinical trials are underway using hydroxychloroquine, an oral drug commonly prescribed to treat rheumatological conditions, which can block autophagy and has antitumor effects in animal models.

Dafna Bar-Sagi, PhD, my colleague at NYU Langone’s Perlmutter Cancer Center and our vice dean for science and chief scientific officer, has found that pancreatic cancer cells create vesicles on their own surfaces to capture proteins floating nearby, pulling them into the cells in a process called macropinocytosis. We are now collaborating to determine if macropinocytosis and autophagy cooperate to fuel cancer cells.

Additional research in my lab is seeking to understand how pancreatic tumor cells rewire their metabolism. This could provide novel entry points for therapeutic attack. We demonstrated that pancreatic tumors require the continued expression of the KRAS oncogene for growth and identified a critical role for KRAS in rewiring glucose metabolism. Furthermore, we have found that pancreatic tumor cells rely on a novel KRAS-dependent metabolic pathway that is critical for redox balance. Blocking any of several enzyme reactions in this pathway disturbed the redox balance and suppressed the growth of human pancreatic cancer cells transplanted to mice.

This novel pathway does not seem to be important for normal cells, which suggests that drugs inhibiting this pathway could block cancer cells’ growth without harming nontumor cells and could also make pancreatic tumors more susceptible to standard treatments such as radiation and chemotherapy. Ongoing work in the lab is seeking to identify additional metabolic targets, with the goal of discovering new drugs to test in clinical trials in patients. In the meantime, we are assessing potential metabolic vulnerabilities in genetically engineered mouse models.

There is reason to be optimistic for the development of improved therapies over the next 5 to 10 years. We are making great progress in understanding the basic science of pancreatic cancer, and there is a huge push to translate these findings into therapies for patients. Targeting metabolism is still in its infancy, but I expect to see more clinical trials in pancreatic and other cancers.

Researchers at NYU Langone Medical Center are taking an approach that
focuses on the unique metabolic adaptations of pancreatic cancer.

NYU Researchers Target Tumor Cell Metabolism in Pancreatic Cancer

It is difficult to overstate the potential for improvements in cancer treatment outcomes based on the stunning advances in our understanding of the molecular basis of the development and progression of malignant disease and the increasing insights into the mechanisms of drug resistance.

The large number of novel antineoplastic drugs in the development pipeline is also testimony to the excitement in the biotechnology community regarding the expanding role of innovative strategies in cancer management.

Unfortunately, the current status of clinical cancer research in the United States falls far short of what is necessary to effectively and efficiently change this amazing opportunity to improve both the quantity and quality of the lives of patients with cancer into an objective reality.

Consider the simple and quite disturbing observation that less than 4% of patients with cancer participate in a clinical trial.

 This most distressing fact needs to be repeated so that its implications can be fully absorbed: the care and outcomes of fewer than 1 in every 25 patients with cancer currently contribute to the generation of the new knowledge that informs the development of fresh management strategies, defines the anticipated short-term and long-term adverse event profiles of novel approaches, and serve as the population base for oncologists employ in conversations with prospective patients and their families regarding the probability of benefit versus risk of harm associated with various treatment options.

Moreover, the 1 in 25 patients who participate in clinical trials fall short of depicting the real world of individuals who require management of their cancers, as multiple analyses reveal a lack of representation of the elderly and those with common comorbidities who have the potential to meaningfully alter the risk-to-benefit ratio for a given strategy. Further, in the absence of such essential data there should surely be serious questions regarding the optimal starting doses or schedules for novel agents and concerns about important contraindications in a given setting such as pre-existing mild/moderate renal, cardiac, or pulmonary dysfunction that remain unknown in the absence of prior clinical trial experience.

And if this picture is not distressing enough, one must add the documented, often inane bureaucracy associated with the current clinical trials paradigm. 

 Does the incredible paperwork required to document why a complete blood count was obtained on day 10 instead of day 8 really add to the validity of the results of a clinical trial? Does the information obtained justify the added costs? This abbreviated list of the multiple serious concerns inherent in the current clinical cancer research domain and its negative impact on the efficient evaluation and development of useful therapeutics have been extensively discussed in the oncology literature—but little has changed.

Overall Survival Poses Problems as Endpoint

Although many reasons can be advanced to explain this unsatisfactory situation, there is a stunning lack of alignment among interested participants in the research domain regarding even the foundation of the problem requiring resolution.

Consider, for example, that some members of the purist academic/university collective continue to believe that the only valid endpoint for approval of a new pharmaceutical agent or strategy is the finding of a statistically significant improvement in overall survival in a phase III randomized trial.

The current status of clinical cancer research in the United States falls far short of what is necessary to effectively and efficiently change this amazing opportunity to improve both the quantity and quality of the lives of patients with cancer into an objective reality.