Aggressive B-Cell Lymphoma
Optimizing CAR T-Cell Therapy and Durability of Response in Aggressive B-Cell Lymphoma
At the 62nd ASH Annual Meeting and Exposition, a number of abstracts focused on strategies to optimize chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed aggressive B-cell lymphoma. Topics of interest included future directions in the development of autologous T-cell therapies and the exploration of the use of novel agents as bridging therapies.
Our featured expert, Frederick L. Locke, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Locke’s clinical perspectives on these abstracts are presented here.
Co-Leader, Moffitt Immuno-Oncology Program
“As soon as it is clear that R-CHOP is not going to be curative, the treating oncologist should consider CAR T-cell therapy. Although this is not FDA approved as a second-line agent, the patient should be referred to a center at this point for a variety of reasons.”
With the US Food and Drug Administration (FDA) approvals of axicabtagene ciloleucel and tisagenlecleucel, we now have CAR T-cell therapies that can result in durable remissions for many patients with relapsed aggressive B-cell lymphoma. This is a significant development. Still, we need to improve upon the outcomes of autologous CAR T-cell therapy use in patients with lymphoma, and there are several different areas of opportunity in this regard.
First, it is worth noting that optimizing the timing of currently available CAR T-cell therapies is, in and of itself, an important opportunity right now. While awareness of these therapies is generally quite good, there is still room for improvement in terms of planning ahead for their use. As soon as it is clear that R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) is not going to be curative, the treating oncologist should consider CAR T-cell therapy. Although this is not FDA approved as a second-line agent, the patient should be referred to a center at this point for a variety of reasons (eg, to account for the vein-to-vein time of autologous CAR T-cell therapy and/or the potential need for consolidative transplantation post second-line treatment).
With an eye toward the future, we also want to better understand why some patients with aggressive B-cell lymphoma achieve long-term remissions with these cellular therapies while others do not. Many studies presented at ASH 2020 explored novel approaches to optimize CAR T-cell therapy and/or to potentially improve durability of response. We were involved in one such study, as reported in abstract 1431. Our goal was to improve the ability of CAR T cells to operate in a deleterious microenvironment of hypoxia, nutrient deprivation, and acidosis. We demonstrated that, in vitro, “metabolically flexible” CAR T cells, with enforced expression of mutant or truncated PGC-1α (a master regulator of oxidative metabolism), enhanced mitochondrial quality control with commensurate function. While further research is necessary, we are hopeful that this strategy might improve the function of autologous T-cell therapies and thereby improve outcomes.
In a different study, we examined the effect of ibrutinib on tisagenlecleucel manufacturing and antitumor efficacy, and we reported our findings at ASH 2020 (abstract 1200). Data supported the feasibility of administering ibrutinib to individuals with diffuse large B-cell lymphoma throughout tisagenlecleucel therapy, and ibrutinib seemed to improve product characteristics favorably; however, additional studies are needed to confirm these findings.
Elsewhere at ASH 2020, the antibody-drug conjugate polatuzumab vedotin (Pola) was the focus of several abstracts, including a retrospective analysis with Pola as a bridging concept to immunotherapies (abstract 1206). Pola has been approved by the FDA for use in combination with bendamustine and rituximab for patients with relapsed/refractory diffuse large B-cell lymphoma. Although oncologists in various settings might utilize novel treatments such as Pola initially, with some thought given to CAR T-cell therapy later on in the disease course, the challenge with this approach is not taking into account the wait time involved with the collection of the CAR T cells. Therefore, I would favor utilizing a treatment such as Pola as a bridge to CAR T-cell therapy, provided there is clear acknowledgment that CAR T-cell therapy use is the ultimate way to achieve an ongoing durable remission.
Yet another exciting development that we are seeing is the prospect of off-the-shelf CAR T cells, meaning that they are ready to go whenever you need them. This would be an advantage if these therapies are proven to be as effective as what we currently have. Autologous CAR T cells take approximately 3 to 4 weeks to manufacture, and a lot can happen for these patients in 3 to 4 weeks.
To summarize, there is a significant amount of ongoing research that we hope will lead to future advancements in CAR T-cell therapy. Additionally, opportunities exist right now to optimize the use of these therapies. It is important to be clear on the eligibility for CAR T-cell therapy, as there may be some misperceptions regarding factors such as age or tumor volume. Further, initiating the referral process early (ie, after the first relapse) will expedite the process if patients do not respond to second-line chemotherapy and are eligible for CAR T-cell therapy.
Atkins RM, Menges MA, Bauer A, Turner JG, Locke FL. Metabolically flexible CAR T cells (mfCAR-T), with constitutive expression of PGC-1α resistant to post translational modifications, exhibit superior survival and function in vitro [abstract 1431]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Chang C-H, Qiu J, O’Sullivan D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229-1241. doi:10.1016/j.cell.2015.08.016
Chavez JC, Locke FL, Napier E, et al. Ibrutinib before apheresis may improve tisagenlecleucel manufacturing in relapsed/refractory adult diffuse large B-cell lymphoma: initial results from a phase 1b study [abstract 1200]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117-1127. doi:10.1182/blood-2015-11-679134
Liebers N, Duell J, Nörenberg D, et al. Polatuzumab vedotin in relapsed and refractory (r/r) large B-cell lymphoma (LBCL): real-world data of the German National Compassionate Use Program (CUP) [abstract 1206]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7
Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
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