Kruti Patel, DO, reviews the advancements, landmark trials, and challenges with CAR T-cell therapy for Cancer Immunotherapy Month.
Over the past several decades, numerous types of immunotherapy have emerged that seek to enhance natural defenses to eliminate malignant cells. These therapies have revolutionized oncology, transforming how certain cancers are treated, but they have also created challenges along the way. A closer look at the developments in immunotherapy may provide a greater understanding of the progress made so far, and the journey ahead.
In the 1990’s, rituximab (Rituxan), an anti-CD20 monoclonal antibody used in hematologic malignancies, was introduced. This revolutionized how lymphomas were treated and became the new standard of care. More progress occurred in the 2010s when more monoclonal antibodies were approved. These include the antibody-drug conjugates gemtuzumab ozogamicin (Mylotarg) and brentuximab vedotin (Adcetris). Both are used in hematologic malignancies, with gemtuzumab ozogamicin targeting anti-CD33 and brentuximab vedotin targeting anti-CD30.
In 2018, blinatumomab (Blincyto) was approved for pediatric acute lymphocytic leukemia (ALL). This CD19-targeted BiTE (bispecific T-cell engager) therapy has been very well accepted, and now approved for relapsed/refractory B-cell ALL in adults. Studies are also in progress for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) where specific T-cell engagers are targeting CD19 or CD20.
Chimeric antigen receptor T-cell (CAR T) immunotherapy was next to emerge among immunotherapy in hematologic malignancies. Early on it was investigated for B-cell ALL in pediatrics targeting CD19. It has now been approved for use in adult relapsed/refractory non-Hodgkins lymphoma, multiple myeloma, and relapsed B-cell ALL. Multiple products are now on the market, including axicabtagene ciloleucel (axi-cel; Yescarta), brexucabtagene autoleucel (brexa-cel; Tecartus), tisagenlecleucel (tisa-cel; Kymriah), lisocabtagene maraleucel (liso-cel; Breyanzi), idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti).These drugs have all been approved in the past decade, and more clinical trials are in progress. Ide-cel, the first CAR T-cell therapy for multiple myeloma, was approved in the past 2 years and has shown encouraging overall survival for this difficult disease.
While results from these breakthrough CAR T therapies are promising, there are challenges to overcome, specifically around the tumor microenvironment, T cell exhaustion, and how to avoid cytokine release syndrome, a toxicity associated with the therapy. Researchers are also hoping to see better outcomes as more specific targets for CAR T are investigated, and many trials are in antigen selection for various hematologic malignancies.
Landmark CAR T Studies That Led to FDA Approvals
There are several important clinical trials for CAR T products that resulted in the drugs being approved, greatly increasing the therapeutic armamentarium against cancer:
Eliana Trial for Tisa-Cel (NCT02435849)1
This trial investigated patients up to 21 years of age with refractory B-cell ALL in their second or later relapse. Patients received fludarabine/cyclophosphamide or cytarabine/etoposide as their lymphodepleting chemotherapy, followed by cell infusion after completing lymphodepleting chemotherapy.
The complete remission rate was 60% and complete remission with incomplete hematologic recovery was 21%. All of these patients were minimal residual disease (MRD) negative. Medium duration of response has not been reached. Tisa-cel, approved for pediatric ALL in 2018, was the first CAR T product approved by the FDA.
Cytokine release syndrome (CRS), a common complication seen in patients receiving CAR T therapy, is noted in most CAR T trials. Some products have higher CRS toxicities than others. In Eliana, CRS of any grade was experienced in 77% of patients. Additionally, 40% of patients experienced neurotoxicity, which was managed with supportive care.
ZUMA-1 (NCT02348216)2 and ZUMA-5 (NCT03105336)3 Trials for Axi-Cel
ZUMA-1 was a phase 1/2 study of axi-cel for patients with non-Hodgkin lymphoma with relapsed/refractory DLBCL third line and beyond. Patients received lymphodepleting chemotherapy fludarabine and cyclophosphamide. The objective response rate was 82%, and out of those, 54% had complete response. ZUMA-5 was a phase 2 study evaluating patients with relapsed/refractory indolent non-Hodgkin lymphoma after failing 2 or more prior lines of therapy. The results are impressive with overall response rate of 92%, and the complete response rate was 74%. Patients were closely monitored for CRS, as grade 3 or above CRS toxicity is always a concern. With axi-cel, the CRS toxicity grade 3 or higher was about 13% in ZUMA-1 and 7% in ZUMA-5; grade 3 or higher neurological events were seen in 28% and 19% on the trials, respectively.
JULIET Trial for Tisa-Cel (NCT02445248)4
The JULIET trial studied tisa-cel, which was previously looked at in pediatric ALL, in adults with relapsed/refractory DLBCL who failed 2 or more lines of systemic therapy. The trial also included patients who transformed to DLBCL from follicular lymphoma.
This was a phase 2 study and the only CAR T trial that included bendamustine as an alternative option for lymphodepleting. Approximately 73% of patients received the fludarabine/cyclophosphamide combination, while 20% received bendamustine because they could not tolerate the aggressive regimen of fludarabine/cyclophosphamide.
The overall response rate was 52%, with complete response of 40%. The CRS toxicity grade 3 or higher was approximately 22%, while neurotoxicity was 12%. This is roughly half of the neurotoxicity seen in the prior ZUMA-1 trial.
TRANSCEND-NHL-001 Trial for Liso-Cel (NCT02631044)5
The approval of the third CAR T, liso-cel, was based on the TRANSCEND-NHL-001 trial. This phase 1 study looked at relapsed/refractory DLBCL for 2 lines or beyond. The objective response rate in this trial was 73%, with a 53% complete response rate. The grade 3 or higher CRS toxicity was 2%, and the neurotoxicity was about 10%, both of which are lower than the other trials mentioned.
The differences in these trials are worthy of further investigation, as the closed stimulatory binding domains, the lymphodepleting chemotherapy, and the vector virus used to engineer the T cells vary among the trials. For axi-cel, the closed stimulatory domain was CD28, and for tisa-cel and liso-cel, the closed stimulatory domains were 41BB/CD33. The changes in these domains reflect the different adverse event (AE) profiles of the products. We are doing a cross trial comparison, but the percentage of neurotoxicity was highest in axi-cel, over the other products. Additionally, tisa-cel and liso-cel are both lentiviruses versus axi-cel, which is a retrovirus.
KarMMa Trial for Ide-Cel (NCT03361748)6
The KarMMa trial is a phase 2 study focusing on ide-cel for relapsed/refractory multiple myeloma. Ide-cel was given to patients that had at least 3 prior therapies for multiple myeloma and had also failed an immunomodulatory agent, an anti-CD38 antibody and a proteasome inhibitor.
Median prior lines of therapy was 6, meaning these patients were heavily pretreated. About 94% had received an autologous stem cell transplant prior to this therapy. Median progression-free survival was about 8.8 months and overall survival was 19.4 months. The overall response rate was 73% and complete response was 33%. While the drug had activity and response, researchers would like to achieve better than a complete response of 33%. Only 5% of patients had grade 3 or higher CRS and 3% had grade 3 neurotoxicity, but no grade 4.
CARTITUDE-1 Trial for Cilta-Cel (NCT03548207)7
There are other CAR T trials currently ongoing in multiple myeloma targeting BCMA. The cilta-cel regimen investigated in the CARTITUDE-1 trial was approved by the FDA in February 2022 for multiple myeloma after patients failed 4 or more lines. Patients had much better response rates compared with ide-cel. An update at the American Society of Hematology Annual Meeting showed an overall response rate of 97.9%, and the duration of response was 21.8 months with median follow-up of 18 months. The CRS toxicity and neurotoxicity were comparable with ide-cel. Investigators also reported about 80% of patients had achieved stringent complete response, which is promising and exciting.
ZUMA-2 (NCT02601313)8 and ZUMA-3 (NCT02614066)9 trials for Brexa-Cel
The ZUMA-2 trial studied brexa-cel indicated in relapsed/refractory mantle cell lymphoma. Seventy-four patients with mantle cell lymphoma enrolled in the trial and had an objective response rate of 85% and a 59% complete response. At median follow-up of 12.3 months, 57% of 60 patients in the primary efficacy analysis were still in remission, 95% objective response and 67% complete response rates. Overall survival was estimated to be 83% at 12 months.
Brexa-cel received approval for adult relapsed/refractory B-cell precursor ALL after investigators published results from ZUMA-3. In ZUMA-3, 54 patients with relapsed B-cell ALL were enrolled, and 71% patient achieved complete remission with or without incomplete hematologic recovery at median follow up of 16.4 months. There was a 12.8-monht median duration of remission, with median relapse-free survival of 11.6 months and median overall survival of 18.2 months. Grade 3 or higher CRS was experienced in 24% of patients and
Challenges of CAR T Cell AEs
Despite the success of CAR T, obstacles remain that make its use challenging. Toxicity continues to be problematic, producing AEs not seen with chemotherapy or other immunotherapies. The 2 biggest toxicities of concern are referred to as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), and CRS that can occur after treatment.
CRS is an inflammatory disease that releases inflammatory cytokines. The trials found patients with CRS had high levels of inflammatory cytokines that can cause cold-like symptoms, and in some cases progress to multiorgan failure, potentially leading to death.
Neurotoxicity or ICAN, which involves neurological AEs, often starts with headaches and confusion, and can lead to full blown seizures and coma. Although there is much to learn about this condition, it is thought to be related to the huge cytokine release that happens when T cells expand into the patient’s body.
Based on current knowledge, guidelines have been developed on how to deal with these toxicities. One medication that has been used for CRS is tocilizumab (Actemra), an IL-6 receptor blocker. If given early when patients experience AEs, they may not progress to full blown CRS. Anakinra (Kineret, an IL-1 receptor antagonist, can be used, as well as siltuximab (Sylvant), another IL-6 receptor antagonist, if the CRS is refractory to tocilizumab. For ICANS grade 3 or 4 neurotoxicity, high doses of dexamethasone are commonly used after making sure there are no other causes for the patient’s change in mental status.
All patients in the trials were started on the prophylactic seizure medicine levetiracetam (Keppra) on the day of infusion to reduce the risk for neurotoxicity. On rare occasions cyclophosphamide, siltuximab and anikara have been used for neurotoxicities with some response. If complications do arise, a multidisciplinary approach is required involving nurses, pharmacists, and neurologists who are educated in how to treat ICAN.
Some promising findings were reported for the ZUMA-1 axi-cel trial, which was expanded as exploratory safety management cohorts.10 Some patients received axi-cel and prophylactic corticosteroids for prevention of neurotoxicity and CRS compared with placebo. Those pretreated with corticosteroids had much lower grade 3 or higher CRS than the placebo; the corticosteroid group had 2% versus 13% with placebo. The neurotoxicity with grade 3 or higher was also less, 17% in the corticosteroid group versus 28% in the placebo group. There were no outcome changes in the disease or overall response rate despite steroid use. Based on these findings, prophylactic corticosteroids can be used, especially for the axi-cel product. However, extrapolating those data to other CAR T products would not be recommended as we need more trials.
Patients in remission after CAR T may also experience long-term toxicities. The majority have cytopenia since they have been heavily pretreated and received lymphodepleting chemotherapy. Some may also have hypogammaglobulinemia. These patients must be closely monitored and given intravenous immunoglobulin as needed.
Other Challenges to Progress
There are other barriers inhibiting CAR T, such as needing better targeting for more effective therapies with less threatening toxicities. Additionally, CAR T cannot be used for AML or solid tumors, as there is limited infiltration in solid tumors and antigen escape, and especially in AML.
A variety of innovative strategies are being investigated. Researchers are trying to engineer more successful CAR T products with improved antitumor activity, decreased toxicity, and increased efficacy in different and broader hematologic malignancies as well solid tumors. There are also trials looking at CAR natural killer (NK) cells instead of T cells that would employ NK cells to target a specific antigen and malignancy.
Another challenge is the length of time required to complete the treatment, which can be up to 4 weeks. With aggressive malignancies, patients tend to get sicker or the disease progresses quickly, so time is of the essence. Researchers are investigating allogeneic CAR T products where T cells are collected from donors and infused into patients. A small risk of graft-vs-host disease would exist since they are allogeneic cells, but the process would be quicker.
Final challenges worth noting area lack oflocal availability andfinancial constraints. CAR T is limited to large academic centers and is not easily accessible to local community hospitals. Because it can be challenging for patients to travel for treatment, the therapy needs to be more available to local communities. Financial barriers may also exist for some patients, as CAR T is expensive.
A Promising Future
Immunotherapy has revolutionized many treatments in hematologic malignancies over the past decade, from monoclonal antibodies to check point inhibitors and specific T cell engagers. Much progress has occurred in that aspect. Now the task is to figure out where each therapy fits the best for the patient. Applying this data in the real world is challenging.
In the years to come, CAR T will likely be combined with checkpoint inhibitors and other immunotherapies in different solid tumors, as well as a range of hematologic malignancies to determine the best outcomes. With the recent approval of CAR T in second line therapy, the door is open for much earlier use of immunotherapy, protecting patients from chemotherapy toxicity. This is an exciting time, and there are many promising treatments available, but we also have a lot to learn in order to adapt and apply this knowledge to best serve patients and the community.
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2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447
3. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X
4. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
6. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850
7. Martin T, Usmani S, Berdeja J, et al. Updated results from CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 549. Accessed June 22, 2022. https://bit.ly/3dchVj1
8. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
9. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8
10. Oluwole OO, Bouabdallah K, Muñoz J, et al. Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Br J Haematol. 2021;194(4):690-700. doi:10.1111/bjh.17527