Advancing therapeutics and augmenting curability in diffuse large B-cell lymphoma (DLBCL) have been very challenging. Although many novel approaches have offered promise and continue to be developed, we have not yet identified a clearly superior approach to R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in the front-line setting.1 Of that subset of patients who are not cured with R-CHOP, the prognosis is poor, with a very low proportion achieving long-term survival.
Consequently, the results of recent studies investigating CD19 targeted chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory aggressive B-cell lymphoma (principally DLBCL) are impressive and welcomed.2,3 This approach involves genetically modifying autologous T cells from patients so they express anti-CD19 CARs and subsequently re-infusing the (expanded) cells directed at CD19 on the tumor cells. The ZUMA-1 trial, published in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, is a landmark validation study in the field, since it is the first multicenter phase II trial evaluating CAR T cells in DLBCL.4
Closer Look at Study Findings
In the ZUMA-1 trial, axicabtagene ciloleucel—anti-CD19 CAR T-cell therapy—was administered to 101 patients after low-dose conditioning chemotherapy. Complete responses were observed in 54% of patients, and at 15 months of follow-up, progression-free survival was 41%. As has been observed in other anti-CD19 CAR T-cell studies, neurologic events and cytokine-release syndrome were the principal toxicities seen, with 28% of patients on study developing grade 3 or higher neurologic toxicity. The complete response rate and progression-free survival are impressive, considering the patient population on the study. All patients had relapsed or refractory aggressive B-cell lymphoma (DLBCL in 76%, primary mediastinal B-cell lymphoma in 8%, and transformed follicular lymphoma in 16%), 69% had received three or more lines of prior therapy, and 26% had a history of primary refractory disease.
Moving forward, there are many challenges for anti-CD19 targeted CAR T-cell approaches, as their emerging role in DLBCL and other B-cell lymphoma therapeutics becomes better defined.— Kieron Dunleavy, MD
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Another published study evaluated an alternative anti-CD19 CAR T-cell construct (CTL019) in a relapsed or refractory population with DLBCL or follicular lymphoma.5 They reported similar outcomes to the ZUMA-1 trial (57% complete response rate in 28 patients), with severe cytokine-release syndrome and encephalopathy also being observed. Interestingly, in the ZUMA-1 trial, CAR T-cell expansion after infusion of cells was significantly associated with response, and those patients who responded had an AUC within the first 28 days after infusion that was 5.4 times higher than that in nonresponders; AUC and peak expansion levels were also significantly associated with the development of neurologic toxicity of grade 3 or higher.
Unanswered Questions Remain
Moving forward, there are many challenges for anti-CD19 targeted CAR T-cell approaches, as their emerging role in DLBCL and other B-cell lymphoma therapeutics becomes better defined. In particular, neurologic toxicity, which is commonly encountered, remains poorly understood, and future biomarker studies need to better probe its etiology to develop strategies that abrogate this toxicity. Identifying a priori which patients will benefit vs those who are unlikely to benefit is a priority for future studies. Do certain subsets of DLBCL particularly benefit from this approach? And how do tumor and microenvironment biologic factors influence tumor control after CAR T-cell therapy, and what role do they have with respect to loss of tumor-surface antigens and persistence of anti-CD19 T cells?6-8 Are there superior targets to CD19, and is there a role for CARs that target multiple B-cell antigens? Can CAR T-cell constructs be further optimized by using different co-stimulatory domains or by modifying other construct regions? There now are many different classes of small-molecule inhibitors that have differential activity within DLBCL subtypes, and a major challenge for future studies is to identify which classes should be combined with adoptive T-cell immunotherapy approaches such as anti-CD19 CAR T cells and how combination strategies should be sequenced to optimize response.9 ■
Dr. Dunleavy is Director, Lymphoma Program, and Co-Director, Microbial Oncology Program, George Washington University Cancer Center, Washington, DC.
DISCLOSURE: Dr. Dunleavy reported no conflicts of interest.
REFERENCES
1. Davies A: Tailoring front-line therapy in diffuse large B-cell lymphoma: Who should we treat differently? Hematology Am Soc Hematol Educ Program 2017:284-294, 2017.
2. Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-549, 2015.
3. Locke FL, Neelapu SS, Bartlett NL, et al: Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther 25:285-295, 2017.
4. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.
5. Schuster SJ, Svoboda J, Chong EA, et al: Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 377:2545-2554, 2017.
6. Shalabi H, Kraft IL, Wang HW, et al: Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma. Haematologica. February 1, 2018 (early release online).
7. Dunleavy K, Steidl C: Emerging biological insights and novel treatment strategies in primary mediastinal large B-cell lymphoma. Semin Hematol 52:119-125, 2015.
8. Fowler NH, Cheah CY, Gascoyne RD, et al: Role of the tumor microenvironment in mature B-cell lymphoid malignancies. Haematologica 101:531-540, 2016.
9. Bollard CM, Tripic T, Cruz CR, et al: Tumor-specific T-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed Hodgkin lymphoma. J Clin Oncol 36:1128-1139, 2018.
