A panel of experts discusses the current state of CAR T-cell therapies and sheds light on the future directions of this therapeutic approach.
Michael Pulsipher, MD
Chimeric antigen receptor (CAR) T-cell therapy has been named the Advance of the Year in the American Society of Clinical Oncology’s (ASCO’s) Clinical Cancer Advances 2018. 1 It’s not hard to understand why. CAR T-cell therapy is unique among treatments because it simultaneously serves as a cell therapy, gene therapy, and immunotherapy. Typically, T cells are extracted from the patient, genetically modified to express a CAR, expanded in vivo, and then reinfused, enabling a patient’s immune cells to fight the cancer. Thus far, remarkable results have been observed in young patients with acute lymphoblastic leukemia (ALL) and adults with lymphoma and multiple myeloma.
During an OncLive Peer Exchange® moderated by Krishna V. Komanduri, MD, a panel of experts discussed the current state of CAR T-cell therapies and shed light on the future directions of this exciting new therapeutic approach, which is currently being investigated in more than 400 clinical trials.2So far, 2 CAR T-cell therapies have been approved by the FDA: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta).3,4 Tisagenlecleucel was approved in late August 2017 for patients 25 years and younger with B-cell precursor ALL that is refractory to treatment or in its second or later relapse.3 Approval was based on the results of the ELIANA trial, which showed a 3-month complete remission rate of 83% and a 6-month probability of survival of 89%.5
Although these results are impressive, the panelists noted that there is not a great need for CAR T-cell therapy in pediatric ALL.
Most of these patients are effectively treated with standard chemotherapy, with cure rates of 80% to 90%, said Michael Pulsipher, MD. That leaves only a small population of patients with refractory disease who might benefit from CAR T-cell therapy. However, the benefits can be significant for this small subset. “By treating these same patients whom we would have put in hospice previously, we now have 75% of them alive at 1 year and more than 60% of them cured—we think—over the long term,” he said.
Pulsipher lamented that tisagenlecleucel must be used off-label in adults older than 25 years. “We desperately need new clinical trials in the adult population to keep going forward, because there’s no doubt this is an active treatment. I have a 72-year-old who’s in remission for ALL with this,” he said.
In mid-January 2018, about a month after this Peer Exchange discussion, the FDA granted priority review for tisagenlecleucel as a treatment for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for or who have relapsed after autologous stem cell transplant.6 The designation was based on results of the phase II JULIET study.
FDA approval of axi-cel came in October 2017.4 It is approved for adult patients with relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy. The treatment can be used for 4 lymphoma subtypes: DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.4
Approval was based on findings from the ZUMA-1 study, which showed an overall response rate of 82% and a complete response rate of 54% after a single infusion of therapy.7 Although these rates were lower than those observed in the pediatric population, they were outcomes for patients who had no other options for potentially curative treatment, the panelists noted.
“You have to remember these patients were not even eligible for an autotransplant, or they had already failed, so this is a population that had a significant unmet need, and these are tremendously exciting results,” said David Maloney, MD, PhD. “There is nothing else that would give this kind of remission in this population,” he added. Furthermore, follow up at 15.4 months indicated that responses were durable, with 42% of patients remaining in complete remission.8A key challenge with CAR T-cell therapy is the adverse event (AE) profile, with cytokine release syndrome (CRS) and neurological toxicity being common, particularly among adults. In the longer term ZUMA-1 data, the incidence of grade ≥3 AEs was 12% for CRS and 31% for neurological toxicity among 101 patients.8 “Almost half of the patients required some type of intervention with either an IL-6 receptor antibody blocker or steroids,” Maloney said.
However, Pulsipher estimated that only 15% to 25% of cases of CRS are severe enough to put patients into the ICU. Despite posing a treatment challenge, this AE is a sign of high-level immune activation and therefore is an indicator of benefit. “We know that patients who have cytokine release syndrome have a better chance of having a good response and having a long-term expression of their CARs,” Pulsipher said. When these toxicities occur, they usually manifest within 2 weeks of administration. “Most neurotoxicity is reversible and patients go back to normal, but it does take several days.”
Neurological toxicity, which may involve confusion, aphasia, mania, and seizures, “is the most frustrating thing to treat because none of our treatments have anything to do with reversing it. It seems to reverse on its own in almost all cases, but we really don’t know the right treatment, and we need breakthroughs in that area,” Maloney said. Other toxicities the panelists warned about include B-cell aplasia and coagulopathy with a very rapid drop in fibrinogen, although these concerns vary significantly by CAR and the population treated.Currently approved CAR T-cell treatments are modified to target the B-lymphocyte antigen CD19, but cells can be modified to target other antigens. “If you can find an antibody that’s directed against a tumor-restricted or relatively restricted target, then that would enable this therapy to potentially treat that cancer. This is why it’s such an exciting field,” Maloney said.
The panelists’ discussion made clear that researchers have only started to scratch the surface of the potential of CAR T-cell therapies. Progress is being made on multiple fronts, from the development of new targeting techniques to CAR T's use across various malignancies. Combinations of CARs or the addition of other agents may also yield improvements in outcome.JCAR017 is a second-generation CAR T-cell therapy in development for relapsed or refractory aggressive B-cell lymphoma. Although it is also a CD19-directed treatment, it has a costimulatory domain of 4-1BB, rather than CD28, and modifies both CD8+ and CD4+ T lymphocytes, returning them to the patient in a 1:1 ratio. “Most of the CARs that have been given to date just collect T-cells from the patient, expand them, put the CAR in, and give them back in the right number, but we found that the types of T cells you put into this matters,” Maloney said.
In the TRANSCEND NHL 001 study, JCAR017 showed a response rate of 81%, with 63% of patients achieving a complete response.9 Although these efficacy data are comparable to those of approved CAR T-cell therapies, safety appears to be improved. Across the full study, 1 patient experienced severe CRS and 11 had severe neurotoxicity (12%).9 “We’re not quite sure whether that’s because of the cell population or just the actual construct of the CAR,” Maloney said, noting the possibility that these toxicities might manifest later and that longer follow-up is needed to better understand this agent’s safety profile. FDA approval of JCAR017 is anticipated in 2019.10
Others have examined targeting different or multiple antigens. “I can envision a future where you come in, donate 10 ccs of blood, and someone makes 3 targeted CARs for whatever your cancer is,” Maloney said. The idea is that targeting more than 1 antigen will lower the risk of antigen loss in B-cell malignancies.
“Dr Crystal L. Mackall, founding director of the Stanford Center for Cancer Cell Therapy, and others are working on combined antigen-targeting approaches,” Komanduri said. Mackall is recruiting patients for a phase I study assessing CD19/CD22 CAR T cells and chemotherapy in pediatric or young adult patients with recurrent or refractory CD19-positive B ALL (NCT03241940).CAR T-cell therapy is being assessed for efficacy in many other malignancies, including hematologic and solid tumors. Thus far, CAR T cells have shown the greatest promise in hematologic malignancies, with an FDA-approved CAR T-cell therapy likely in multiple myeloma in the near future. Although many drugs are available to treat multiple myeloma, none are currently curative, Maloney noted.
“BCMA [B-cell maturation antigen] is a target expressed on plasma cells in many cases of multiple myeloma. We’re starting to see exciting results from several direct companies and groups targeting this,” he said. “We’ve seen response rates in the 50%-to-100% range, but we really need to see real data on that in terms of the stringency of the complete remissions,” he said, noting that we are just at the beginning of BCMA trials. Nevertheless, preliminary clinical data from the ongoing phase I CRB-401 study have led to a breakthrough therapy designation for bb2121, an anti-BCMA CAR T-cell therapy, and priority medicines eligibility from the European Medicines Agency.11
Acute myeloid leukemia (AML) is another hematologic malignancy with a great unmet need. “Despite our very best efforts with transplantation and intensive therapies, we still lose half of our AML patients,” Pulsipher said. “We all know that CARs should work, but we have to find the right targets,” he said, noting that a few studies are currently open and showing some activity. He hopes that the next 2 years will yield CAR T-cell success in AML.
Current AML studies are largely focusing on CD33-directed CAR T cells, although other antigens are also being assessed. Unlike other hematologic malignancies, AML might prove more problematic because treatment is likely to destroy the bone marrow, making transplantation an essential part of treatment. However, transplantation could not be undertaken while a patient is experiencing CRS. To avoid this challenging scenario, some researchers are examining whether intracellular antigens could serve as better targets. One such antigen currently being assessed is WT1. With this approach, a T-cell receptor—transduced cell is used, rather than a typical CAR.
“This approach is pretty much in its infancy, and it doesn’t seem to have quite the potency of a CAR, where we can make literally kilograms of tumor go away in some patients,” Pulsipher said. “Where this treatment seems to be better at this point is in potentially preventing relapse in highrisk patients in the allogeneic setting,” he added. However, more data are needed to draw definitive conclusions.In addition to combining multiple CARs to target different antigens, researchers are looking at whether adding other agents to CARs can improve outcomes. One potential strategy is to add checkpoint inhibitors to CAR T-cell therapy.
“We’ve used the strategy to rescue patients who are having progressive disease during the early phases of CAR T-cell therapy, while there’s actually expansion of T cells in the blood,” said Stephen J. Schuster, MD, noting he and his colleagues authored a report on this approach that was published in Blood.12
“During the early phases of CAR T-cell therapy, the patient was having expansion of CAR cells that were taking on a progressively exhausted phenotype. The patient was treated during progression with pembrolizumab, and we saw a reversal of phenotype and logarithmic expansion of the CAR cells. So, it’s possible that in some patients who are failing because of T-cell exhaustion, you can reverse the process with a checkpoint inhibitor,” he said.