CAR Therapy Era Moves Forward With Much Excitement, Lingering Questions

CAR T-cell therapies have generated considerable enthusiasm in the oncology community since the first FDA approval in 2017. From a clinical standpoint, these therapies have significantly improved outcomes in disease settings where the outlook for patients has historically been murky at best, experts say. At the same time, however, key questions about translating these therapies into clinical practice and extending their use into solid tumor types remain unresolved.

As CAR therapies reach the 5-year milestone in clinical practice, OncologyLive^® spoke with experts in the field, including several prominent investigators who led the way in shaping these novel therapies, to gauge their opinions about the impact these agents have had and the prospects for the future.

“I would liken the last 5 years to an Atlantic crossing in a sailboat: The boat is tacking with the wind and not moving in a very straight line but heading in the right direction,” said Bruce A. Feinberg, DO, an oncology health care expert who is vice president and chief medical office at Cardinal Health Specialty Solutions in Dublin, Ohio.

“With these treatments, we are seeing that there is not only the ability to enable the immune system to recognize the cancer, but that recognition of the cancer by the T cells seems to have some permanence because the manufactured T cells act like a type of sentinel on guard for reemergence. The result is a therapeutic that addresses the immediate disease burden while retaining a memory for future reemergence, similar to how vaccination works,” Feinberg said.

“However, CAR T-cell [therapies] come at a high price with significant clinical and financial toxicities,” Feinberg noted. “Additionally, the logistical burden in a fragile ill patient is considerable. A CAR T [therapy] is not a drug that can be kept on the shelf and administered on demand; it has to be manufactured from the patient’s own blood cells, a process requiring time and relocation to an approved center.”

David L. Porter, MD, who helped pioneer the use of CAR T-cell therapies in leukemias a decade ago, provides a similar perspective. Porter is director of Cell Therapy and Transplantation and the Jodi Fisher Horowitz Professor in Leukemia Care Excellence at Penn Medicine in Philadelphia, Pennsylvania.

“The impact has been dramatic,” Porter said in an interview with OncologyLive^®. “I have no doubt that CAR T cells are curing people who previously had incurable cancers. For those people, when it is working, the impact has been absolutely lifesaving. The big issue is that when it works, it works amazingly well, but it still is not working often enough—at least in those patients with far advanced relapsed/refractory [R/R] disease. There is a tremendous amount of effort trying to make the current CAR T-cell approaches both safer and more effective.”

To date, the FDA has approved 6 CAR T-cell therapies, all for hematologic malignancies, starting with the approval of tisagenlecleucel (tisa-cel; Kymriah) in 2017 for patients up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse (Timeline^1-13). The roster includes 4 CARs that target CD19 and 2 directed at BCMA.¹

These treatments are part of a diverse field of cellular therapies in development not only for oncology indications but also for a range of other diseases.^1,14 Overall, there are more than 2700 active cell therapies in the pipeline worldwide for oncology indications, including for other types of agents besides CAR T cells, such as those that leverage tumor-infiltrating lymphocytes and T-cell receptors.15 Several therapies are in the later stages of clinical studies, and other treatments are being developed through the FDA’s Regenerative Medicine Advanced Therapy (RMAT) pathway (Table).^16-31 The RMAT designation, which was established in 2016 through the 21st Century Cures Act, is intended to expedite the development of innovative biologics products.³²

In February 2021, lisocabtagene maraleucel (liso-cel; Breyanzi) became the first therapy approved through the RMAT pathway, followed by 2 other therapies for nononcology indications.³³ As of mid-October 2022, the agency had granted RMAT status to 79 therapies for a range of diseases.

Current Impact of CAR Therapies

The introduction of CAR T-cell therapies has made a notable impact on the treatment protocols for patients with refractory large B-cell lymphoma (LBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and acute lymphoblastic leukemia (ALL).³⁵ CAR T-cell therapies have displayed extraordinarily high response rates in pivotal clinical trials. For instance, they exhibited overall response rates (ORRs) as high as 92% in patients with R/R FL or MZL treated with axicabtagene ciloleucel (axi-cel; Yescarta) during the ZUMA-5 study (NCT03105336) and 93% in patients with R/R MCL who received brexucabtagene autoleucel (brexu-cel; Tecartus) in the ZUMA-2 study (NCT02601313). Complete response rates (CR) have ranged from 33% to 67% in studies that paved the way for approvals throughout this class of agents.³⁵

There also have been cases of long-term remissions achieved with CAR T-cell agents. In an analysis published in Nature, investigators from the University of Pennsylvania highlighted 2 patients with chronic lymphocytic leukemia who have remained in remission more than 10 years after their initial infusion. Both patients displayed detectable, highly activated CD4-positive CAR T cells at least a decade after remission.³⁶

In another case, a pediatric patient with ALL treated at Children’s Hospital of Philadelphia who experienced multiple relapses following standard therapy has remained in remission for more than 10 years after receiving CAR T-cell therapy. The patient was treated at age 6 years during the first phase 1 trial of CAR T-cell therapy in pediatric patients with ALL.³⁷

Despite these promising findings, the placement of CAR T-cell therapies in the treatment paradigm of hematologic malignancies is still in flux. So far, this class of therapies has been approved by the FDA in the second-line or later settings. However, some experts believe that will change in the near future.

“What is remarkable, at least in the setting of B-cell malignancies, is that [CAR T-cell agents] have been shown to be a viable approach to treating patients who would otherwise have very few other treatment options available,” Renier Brentjens, MD, PhD, said in an interview with OncologyLive^®. “We can say that we have significantly improved the outcome of these heavily refractory patients. What impact it would have if we moved this therapy further up the line is being investigated. It is not unreasonable to think that those results will be certainly as good, if not better than, as what we currently see in the patients who are treated after having received multiple different chemotherapy regimens.”

Brentjens is deputy director, chair of the Department of Medicine, and the Katherine Anne Gioia Endowed Chair in Cancer Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York. He is known in the CAR T-cell community for initiating the first preclinical studies with results that displayed the clinical potential of genetically modified autologous T cells to target the CD19 antigen. He was able translate his research into the clinical setting for patients with relapsed CD19-positive hematologic malignancies. His current research focus includes exploring novel CAR targets such as the GPRC5D protein in multiple myeloma.³⁸

Porter also is optimistic that CAR T-cell agents will eventually find a more consistent place in frontline settings for hematologic malignancies. “One of the more exciting aspects [of these agents] is an interest and movement in the field to use these therapies earlier in the course of disease,” Porter said. “If they are potentially curative, why wait until we have exhausted everything else? It [has been] shown that there not only is an interest in moving the field in that direction, but that it was effective, at least in some cases. That is spurring more and more interest in developing these therapies earlier in the course of the disease.”

Earlier Use in Treatment Timeline

Investigation into CAR T-cell agents’ safety and efficacy in the first-line setting of hematologic malignancies is underway. There are multiple clinical trials in progress in various disease settings and some agents have been approved for earlier use in the treatment timeline.

In April 2022, axi-cel was approved for the treatment of adult patients with LBCL that is refractory to first-line chemoimmunotherapy or who relapse within 12 months of first-line chemoimmunotherapy.¹¹ In October 2017, axi-cel became the second CAR therapy to gain FDA approval, with an indication for treating adults with R/R LBCL after 2 or more lines of systemic therapy.³

The latest indication was supported by findings from the phase 3 ZUMA-7 trial (NCT03391466) in which patients with LBCL that was R/R following first-line chemoimmunotherapy received either axi-cel (n = 180) or standard-of-care chemoimmunotherapy with autologous stem cell transplant if indicated (n = 179).¹¹

The median event-free survival (EFS), the primary end point of the study, was 8.3 months (95% CI, 4.5-15.8) in the axi-cel arm compared with 2.0 months (95% CI, 1.6-2.8) with standard care at a median follow-up of 24.9 months. That translated into an HR favoring CAR therapy of 0.40 (95% CI, 0.31-0.51; P < .001). The ORR with axi-cel was 83%, including a 65% CR rate, compared with a 50% ORR with a 32% CR for standard therapy (P < .001).³⁹

In June 2022, liso-cel gained FDA approval for treating adult patients with LBCL whose disease is refractory to first-line chemoimmunotherapy, who relapsed within 12 months of that therapy, or whose disease is R/R after first-line chemoimmunotherapy and who are not eligible for hematopoietic stem cell transplantation (HSCT).¹³ The indication was based on findings from the phase 3 TRANSFORM trial (NCT03575351). Patients were randomly assigned to receive either the standard of care of 3 cycles of intravenous salvage immunochemotherapy (n = 92) or liso-cel (n = 92) in 2 sequential doses. Treatment with the CAR T-cell product significantly improved EFS compared with the standard of care. At a median follow-up of 6.2 months, the median EFS with liso-cel was 10.1 months (95% CI, 6.1-not reached) vs 2.3 months (95% CI, 2.2-4.3) with standard of care (HR, 0.35; 95% CI, 0.23-053). The ORR was 86% with liso-cel, including a 66% CR rate, compared with 48% and 39%, respectively, for standard therapy.⁴⁰

However, tisa-cel did not demonstrate superiority over standard-of-care salvage chemotherapy plus autologous HSCT in the phase 3 BELINDA trial (NCT03570892). The study enrolled patients with aggressive B-cell non-Hodgkin lymphoma that relapsed or progressed within 1 year of initial treatment.

Efficacy-evaluable patients who received the CAR T-cell agent (n = 162) experienced a median EFS of 3.0 months (95% CI, 3.0-3.5) vs 3.0 months (95% CI, 2.9-4.2) for participants treated with the standard of care (n = 160). The HR with tisa-cel was 1.07 (95% CI, 0.82-1.40; P = .61). Moreover, the ORRs after week 12 assessment were 46.3% (95% CI, 38.4%-54.3%), including a 28.4% CR rate, with tisa-cel vs 42.5% (95% CI, 34.7%-50.6%) with a 27.5% CR rate with standard therapy.⁴¹

Despite these disappointing findings, there are other CAR T-cell agents in the frontline setting that have been displaying encouraging results. Perhaps the most notable first-line trial is the ongoing phase 2 ZUMA-12 study (NCT03761056). The trial is evaluating axi-cel in treatment-naïve patients with high-risk LBCL. It is the first prospective phase 2 trial to examine CAR T-cell therapy as part of first-line treatment for this patient population, study authors wrote.

Findings from the primary efficacy analysis of ZUMA-12 showed that evaluable patients (n = 37) achieved an ORR of 89% (95% CI, 75%-97%), including a CR rate of 78%. The trial met its primary end point of CR rate. Investigators noted that the agent was highly effective as first-line therapy for high-risk LBCL and that further investigation comparing it with chemoimmunotherapy is warranted.⁴²

“[ZUMA-12] showed a very encouraging result in in terms of the percentage of patients that stayed in remission,” David G. Maloney, MD, PhD, medical director of Cellular Immunotherapy and the Leonard and Norma Klorfine Endowed Chair for Clinical Research at Fred Hutch Cancer Center in Seattle, Washington, said in an interview with OncologyLive^®. “It was not a randomized study. It is an exploratory study. But I believe it will form the basis for future trials, trying to use [CAR T-cell therapy] as a part of frontline therapy."

Therapeutic and Logistical Challenges

One of the major drawbacks with CAR T-cell agents has been the incidence of toxicities, particularly cytokine release syndrome (CRS), according to a 2019 analysis of data across clinical trials. CRS usually occurs within a week of infusion with a CAR T-cell therapy, and the rate of any grade CRS can be as high as 93% in patients with lymphoma or leukemia. Patients enrolled in early clinical trials using CAR T-cell therapies required intensive care management at a rate of nearly 50%.⁴³

“When CAR T cells were first developed, we did not understand CRS as well,” Porter said. “It was, and is, a major safety issue. But there has been incredible progress in managing the toxicity of CAR T cells [and] actually preventing it. We understand the biology better. A major challenge is to make the [therapies] safer. There has been great progress to deal with that challenge. As [CAR therapy] becomes safer, as safe, and maybe even safer than conventional therapy, there is no limit to how and where you can use it.”

Another problematic adverse effect (AE) associated with CAR T-cell therapy is neurotoxicity, commonly in the form of immune effector cell–associated neurotoxicity syndrome (ICANS). ICANS arises in a significant percentage of patients who are treated with CD19-targeted CAR T-cell therapies and can be life-threatening and even fatal. In pivotal clinical trials, any-grade ICANS rates ranged from 23% to 67% in adults with R/R B-cell lymphoma and from 40% to 62% for patients with R/R B-cell ALL.⁴

Due to the complex and time-consuming nature of manufacturing CAR T cells, as well as their cost, the uptake and administration of these therapies on a broad scale has proved difficult, especially at the community level. There are approximately 150 medical centers in the United States that are certified to offer at least 1 CAR T-cell therapy. The vast majority of these are academic medical centers in urban areas, potentially making access a challenge for patients who do not live close enough to a center.^44,45

“At this stage, it is probably not the time to move [CAR T-cell agents] to smaller centers because they may not have the clinical expertise [with the types of toxicities involved] that would be needed to treat these patients,” Brentjens said. “As we get better, and as the algorithms for managing these toxicities become simpler, one could envision that ultimately even smaller community hospitals could offer these therapies. But that is still several years away.”

Besides toxicity concerns, CAR T-cell therapies remain expensive. In a study published in JAMA Network Open, investigators used a decision-tree model to estimate the cost of the therapy from the healthcare practitioner perspective using data from publicly available databases and published studies.46 Findings showed that the estimated total cost of care for treating a single adult patient with R/R LBCL with a CAR T-cell therapy was $454,611 (95% CI, $452,466-$458,267) in the academic hospital inpatient setting and $421,624 (95% CI, $417,204-$422,325) in the nonacademic specialty oncology network setting.⁴⁶

However, Feinberg said, cost has not been a barrier for gaining authorization for CAR therapy. “As part of our research, talking directly to both physician peers and to the centers evaluating these patients, price has not been the stumbling block for patients who meet the treatment criteria,” Feinberg said.

At the same time, he said, “efforts to try to look at novel payment strategies like a value-based care design have not really taken hold."

Potential for Cellular Therapies

Beyond moving into earlier lines of therapy in hematologic malignancies, many experts see breaking into the treatment paradigm in solid tumors as the next step in the evolution of CAR T-cell therapies. There are currently no FDA-approved CAR T-cell agents for the treatment of solid tumor malignancies.⁴⁷

“In solid cancers, we are finding that the T-cell trafficking to the tumors may be different than in hematologic malignancies,” Maloney said. “It is likely a more hostile environment for the CAR T cells in that the tumor is actively trying to suppress the T-cell proliferation. We likely have to add other agents to the CAR T cells in ourengineering to make them able to signal and function despite the hostile environment of the tumor.”

“Solid tumors are much more complex in the tumor microenvironment,” Carl H. June, MD, said in an interview with OncologyLive^®. “Just for the CAR T cell to get in there and then have the amazing proliferation that we see in blood cancers, that has not usually happened, although we are seeing times when that does occur.”

June, a 2015 Giants of Cancer Care^® award winner in the immuno-oncology category, published groundbreaking research into cellular therapies in hematologic malignancies that led to the initial approval for tisa-cel. He is the Richard W. Vague Professor in Immunotherapy, director of the Center for Cellular Immunotherapies, and director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania.

Several phase 1 clinical trials are in progress evaluating the safety and efficacy of CAR T-cell agents, both as monotherapies and part of combination regimens, in solid tumor malignancies. CAR T-cell therapies are being examined in glioblastoma as well as gastrointestinal, renal, prostate, ovarian, and thoracic cancers.⁴⁷

The CAR T-cell therapies being studied in solid tumors have a much wider array of targets compared with the currently approved agents in hematologic malignancies, which only target either CD19 or BCMA. Agents in the space are being developed to target disease-specific antigens such as HER2, EGFRvIII, CEA, and GPC3.⁴⁷

In a first-in-human phase 1/2 trial (NCT04503278), the investigational carcinoembryonic antigen claudin 6 (CLDN6)–directed CAR T-cell therapy BNT211-01 displayed clinical activity both as monotherapy and in combination with a CLDN6-encoding mRNA vaccine in patients with CLDN6-positive R/R advanced solid tumors. Investigators reported results for 21 evaluable patients involving 7 solid tumor types at the European Society for Medical Oncology Congress 2022 in September.⁴⁸

At the June 15, 2022, data cutoff date, the ORR was 33%, including 1 patient who experienced a CR. Additionally, 7 patients achieved stable disease, and the disease control rate was 67%. The population was heavily pretreated, with a median of 4 (range, 3-9) prior lines of therapy. Responses were particularly encouraging among the 13 participants with testicular cancer; the ORR for these patients was 33%, including 1 CR.⁴⁸

Investigators noted that these results, although promising, cannot be used to draw any significant conclusions at this time due to the small number of patients enrolled and the early stage of the data.

A primary barrier to the development of CAR T-cell agents in the solid tumor space, beyond the complexity of the tumor microenvironment, is the lack of specificity of the agents to affect the target antigen. Fatal AEs have been reported due to CAR T-cell agents damaging healthy tissues that also expressed the target antigen. Additionally, the heterogeneity of tumor antigens in solid tumors compared with that of hematologic malignancies, leads to inconsistent and incomplete malignant cell death.⁴⁷

“Blood-based cancers have historically always been the first pursuit in new drug and new treatment development because of the access to tumor cells circulating in the blood,” Feinberg said. “Blood-based cancers were the first to receive chemotherapy, then high-dose treatments, bone marrow and stem cell transplantation, and CAR T. Each technology eventually progressed to be useful against solid tumors.

“If and when CAR T is approved for solid tumors, the US-accredited centers performing CAR T would be overwhelmed,” he added. “We are at the beginning of a revolution in therapeutics with newer therapies that will be more effective, less toxic, and allow for broader application across patients and treatment sites. We need to be prepared for the numbers of patients for which we will have to think about its impact on our health care ecosystem, both financially as well as operationally.”

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