This is perhaps the most exciting era in the treatment of hematological malignancies because of the recent developments in chimeric antigen receptor (CAR) T cell therapies. Two major presentations— the latest analysis of the landmark trial (ZUMA-1) by Neelapu et al, as well as the primary analysis of the phase II global JULIET study by Schuster et al, were presented at the 59th American Society of Hematology (ASH) Annual Meeting.1,2 These new longer-term clinical data illustrated that remissions were durable in approximately half of the patients with relapsed or refractory (r/r) B-cell lymphomas, who have no curative treatments available. Along the heated race of tisagenlecleucel and axicabtagene ciloleucel (axi-cel), a number of CAR T studies were also presented in this year’s meeting, with the overarching takeaway message that this approach is emerging as a real viable option for patients with advanced hematological malignancies.
CAR T cell therapy is a type of adoptive immunotherapy, in which the patients’ T cells were genetically engineered to express a CAR or T cell receptor, thus enabling their cytotoxic specificity to be redirected towards tumor cells.3 This novel strategy is rapidly emerging as a promising treatment modality for patients with otherwise limited options. In August 2017, the FDA approved the first-in-class therapy, tisagenlecleucel, for patients up to 25 years of age with r/r acute lymphoblastic leukemia (ALL).4 Though the indication is narrow, the results are striking: 83% of the 63 evaluable patients went into remission in 3 months after drug administration. Shortly following the approval of tisagenlecleucel, the second CD19-specific CAR T cell therapy, axi-cel, was also approved by the FDA for the treatment of adults with r/r diffuse large B cell lymphoma (DLBCL), based on a complete response (CR) rate of 51% in ZUMA-1 trial.5
Given the success in earlier studies, the recent CAR T studies have shifted to ask a number of important questions: Could the remarkable response rates of tisagenlecleucel be attained in lymphoma? Will the responses to CAR T cell therapy be durable as we have more follow-up? What about the tolerability in long-term? ASH 2017 provided a glimpse of the longer-term outcome data, and the potentials of cellular application in clinical settings.
JULIET: Tisagenlecleucel in r/r DLBCL
JULIET is a single-arm, open-label phase II trial examining tisagenlecleucel in patients with r/r DLBCL.1 “What is unique about this trial is that it was global, so we used T cells that were collected locally, cryopreserved and shipped all over the world. This was 27 centres in ten countries on four continents, and the results will demonstrate that this technology is exportable and can be safely administered in multiple centres by adequately trained personnel,” said the lead investigator, Dr. Stephen J. Schuster from the University of Pennsylvania.6
Analysis of 81 patients followed for at least 3 months found that the best objective response rate (ORR) was 53.1% (95% CI: 42%-64%; p<0.0001), with 39.5% of them achieving complete response (CR) (Figure 1),1 which was substantially higher than the historic response rates of ~20% in this patient population.6 More importantly, most patients with responses at 3 months presented ongoing responses at 6 months (Figure 1).1 The ORR at 3- and 6-month was 38% and 37%, respectively (the corresponding CR rates were 32% and 30%).1
Although the median follow-up was just 5.6 months in JULIET,6 Dr. Schuster anticipated that the remission may be as durable as in the case series study that was reported in the New England Journal of Medicine (NEJM) previously.7 In that study, the CR rate was 57%, and all patients who were in complete remission by 6 months (DLBCL, n=6; follicular lymphoma, n=10) remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction.7 “Taken together, our data from both trials show that most patients who are in remission at three months stay in remission,” commented Dr. Schuster.8
ZUMA-1: Axi-cel in refractory B-cell non-Hodgkin’s Lymphoma (B-NHL)
An updated analysis of ZUMA-1 was also reported at the meeting, which was presented by Dr. Sattva S. Neelapu of the University of Texas MD Anderson Cancer Center. The results were published simultaneously in the NEJM, alongside the article of Schuster et al.9 “Long-term follow-up of ZUMA-1 confirms that these responses can be durable, and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” said Dr. Neelapu.8
As of August 11, 2017, the phase I/II ZUMA-1 trial has enrolled 108 patients with refractory B-NHL.2 The phase II cohort (n=101) included 77 patients with refractory DLBCL and 24 patients with refractory primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The combined analysis of the phase I/II cohorts demonstrated an impressive best ORR of 82%, with a CR rate of 58%. (Figure 1).9
Notably, responses to axi-cel were highly durable. After a median follow-up of 15.4 months, 56% of patients were still alive, 42% of patients remained progression-free, and 40% of patients exhibited no evidence of cancer.10 The median duration of CR had not been reached, though additional results from the phase I component of ZUMA-1 may provide further support of the extended duration of response to CAR T cell therapy. Among the 7 patients treated with axi-cel in the phase I trial, 3 patients (43%) had ongoing CR after 24 months of follow-up.9 “This is what the field has been waiting for, and this will serve as a benchmark for other products,” said Dr. David Maloney from Fred Hutchinson Cancer Research Center in Seattle.8
No new safety signals in JULIET and ZUMA-1
Early CAR T studies have showed that the treatment was associated with unique acute toxicities, namely cytokine release syndrome (CRS) and neurotoxicity, which can be severe, or even fatal in rare cases.7,9 However, the latest safety analysis of JULIET and ZUMA-1 have suggested that the CAR T products may be administered safely, with no new signals of toxicity during longer follow-up (Table 1).1,2 “Late onset adverse events [AEs] were primarily infections and manageable,” said Dr. Neelapu, “there was no late-onset CRS or neurologic events due to anti-CD19 CAR T cells.”10
While the serious acute toxicities speak to the need for ongoing research to improve tolerability, CAR T cell therapy is undoubtedly the “new standard of care for the patients who receive these therapies,” wrote Dr. Eric Tran and colleagues in the accompanying NEJM editorial.11 Indeed, when compared with conventional therapy, “the risk [of treatment-related deaths] is about 1% to 2%, but these patients have a 100% risk of dying from their lymphoma,” said Dr. Maloney.8
The development of CAR T cell therapy is still in its infancy, and many avenues for improving this treatment are currently being pursued. Several additional studies presented at the meeting may provide further support for the emerging role of CAR T cell therapy across hematologic malignancies (Figure 2).
Considering that two types of T cells, CD8+ cytotoxic T cells and CD4+ helper T cells, are important for an optimal T cell response against malignancy, the administration of lisocabtagene maraleucel, which is composed of a defined 1:1 ratio of CD4+:CD8+ CAR T cells, is currently being investigated in NHL patients in the phase I TRANSCEND NHL 001.12
In addition, novel targets are being explored, potentially expanding the indications for CAR T cell therapy. Two new CAR T cell therapies directed against the B cell maturation antigen (BCMA), bb2121 and CART-BCMA, yielded promising results in heavily pretreated multiple myeloma patients.13,14
Work is also underway to potentially overcome the issue of resistance. It appears that the loss of CD19 and the gain of PD-L1 expression were the two mechanisms of CAR T failure in the ZUMA-1 trial.2 Combinational approaches with CAR T cells that are directed at multiple targets or the addition of PD-1/PD-L1 monoclonal antibodies are currently being studied, and they may represent a new wave of highly personalized therapy.10
Simply put, exciting times lie ahead. While lymphoma is leading the way in this arena, it is foreseeable that the development of CAR T cell therapy will continue to move forward and may hopefully reshape the treatment approaches in other difficult-to-treat hematologic malignancies in the future.
1. Schuster SJ. Bishop MR, Tam CS, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Presented at the 59th American Society of Hematology (ASH) Annual Meeting. 2017; Atlanta, GA. Abstract 577.
2. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: A pivotal trial of axicabtagene ciloleucel (Axi-Cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma. Presented at the 59th American Society of Hematology (ASH) Annual Meeting. 2017; Atlanta, GA. Abstract 578.
3. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy- assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
4. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA News Release. 2017 (Accessed February 4, 2018, at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm574154.htm).
5. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA News Release. 2017 (Accessed February 4, 2018, at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm581296.htm).
6. Data from the JULIET trial of CTL019 for relapsed or refractory diffuse large B-cell lymphoma. Ecancer conferences. 2017 (Accessed February 4, 2018, at http://ecancer.org/conference/942-ash-2017/video/6586/data-from-the-juliet-trial-of-ctl019-for-relapsed-or-refractory-diffuse-large-b-cell-lymphoma.php).
7. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017; 377(26):2545-2554.
8. CAR T Cells in Advanced R/R Lymphoma: Keeping Patients Alive. Medscape. 2017 (Accessed February 4, 2018, at https://www.medscape.com/viewarticle/889874_print).
9. 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.
10. Axicabtagene ciloleucel for patients with non-hodgkin lymphoma. Ecancer conferences. 2017 (Accessed February 4, 2018, at http://ecancer.org/conference/942-ash-2017/video/6584/axicabtagene-ciloleucel-for-patients-with-non-hodgkin-lymphoma.php).
11. Tran E, Longo DL, Urba WJ. A Milestone for CAR T Cells. N Engl J Med. 2017;377(26):2593-2596.
12. Abramson JS, Palomba ML, Gordon LI, et al. High Durable CR Rates in Relapsed/Refractory (R/R) Aggressive B-NHL Treated with the CD19-Directed CAR T Cell Product JCAR017 (TRANSCEND NHL 001): Defined Composition Allows for Dose-Finding and Definition of Pivotal Cohort. Presented at the 59th American Society of Hematology (ASH) Annual Meeting. 2017; Atlanta, GA. Abstract 581.
13. Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Resultsfrom a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Presented at the 59th American Society of Hematology (ASH) Annual Meeting. 2017; Atlanta, GA. Abstract 740.
14. Cohen AD, Garfall AL, Stadtmauer EA, et al. Safety and Efficacy of B-Cell Maturation Antigen (BCMA)- Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM). Presented at the 59th American Society of Hematology (ASH) Annual Meeting. 2017; Atlanta, GA. Abstract 505.