The Future of Cell Therapy: Optimizing the CAR to the Disease in B-Cell Malignancies

Over the past 20 years, increased understanding of the biological mechanism of disease has led to improved treatment options for all malignancies. Within each disease subtype, we have molecularly characterized tumors and developed specific treatment algorithms to optimize patient outcomes.

Among B-cell malignancies, there is significant heterogeneity in both treatment approach and clinical outcomes among the varying subtypes. Diseases such as diffuse large B-cell lymphoma (DLBCL) are often curable and treated with anthracycline-based combination chemoimmunotherapy,¹ whereas other B-cell malignancies such as chronic lymphocytic leukemia (CLL) are thought to be largely incurable and treated with oral agents.² Even among traditional chemotherapeutics, different drugs have varying sensitivity based on histology. For instance, bendamustine is favored in the treatment of follicular lymphoma,³ whereas high-dose cytarabine has unique importance in the treatment of mantle cell lymphoma (MCL)⁴; however, neither plays a significant role in the treatment of DLBCL. Through series of clinical trials, the treatment approach to DLBCL has been refined in an iterative fashion.

Moving Beyond One Size Fits All

CD19 chimeric antigen receptor (CAR) T-cell therapies have revolutionized the approach to relapsed, refractory B-cell malignancies, with efficacy and approval in B-cell acute lymphoblastic leukemia (ALL), MCL, follicular lymphoma, CLL, and DLBCL.⁵ As CD19 is an antigen present throughout the B-cell lineage, the approach to date has been one size fits all, using similar murine-based, CD19-targeting CAR T-cell constructs for all types of B-cell malignancies. However, CD19 antigen density varies significantly among patients with B-cell lymphomas, impacting CAR T-cell reactivity and potentially clinical outcomes.⁶ Loss of CD19 contributes to a subset of relapsing patients,⁷ and despite high objective response rates, most patients will eventually relapse after CD19 CAR T-cell therapy. Although differences in toxicity profiles and efficacy may drive decision-making among CD19 CAR T-cell treatments, is it time to rethink our CAR strategy and optimize a CAR product to specific characteristics of the targeted B-cell malignancy?

“As the race continues to determine the optimal delivery platform, manufacturing parameters, and targets, it may be time to consider that there may be an ideal CAR design for each B-cell malignancy.”

— NIRAV N. SHAH, MD, MSHP

Tweet this quote

Our group recently published outcomes for a dual-targeted, lentiviral, anti-CD20/anti-CD19 (LV20.19) CAR T-cell product in relapsed, refractory MCL.⁸ Unlike other B-cell malignancies, MCL is defined by bright CD20 status and is known to have high CD20 antigen density and clinical responsiveness to CD20-targeting agents.⁹

In a single-center study of 17 patients with multiply relapsed MCL and a median of four prior lines of treatment who were enriched for high-risk features (eg, p53 aberrations), we reported an objective response rate of 100%, with just two relapses at a median follow-up of 16 months. The safety profile was favorable, with low rates of grade ≥ 3 cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome. Among the two relapsing patients, one patient was CD20-negative prior to infusion, perhaps limiting the durable efficacy of the CAR in this particular case.

Correlative studies demonstrated potentially higher in vitro killing efficiency of dual-targeted LV20.19 CAR T cells in comparison to single-agent CD19 CAR T cells. It is possible that in MCL, with high CD20 antigen density, targeting this protein may be more impactful than in other B-cell histologies. Several dual-targeted CAR T-cell therapies targeting CD20 and CD19 are asking similar questions (ClinicalTrials.gov identifiers NCT04989803 and NCT05826535).

Antigen Targeting and Variability in Disease Response

With increasing numbers of clinical trials, we are starting to appreciate the importance of antigen targeting and variability in disease response. Early work with CD22 CAR T-cell therapy in patients with post-CD19, relapsed DLBCL and B-cell ALL demonstrated significant efficacy—even among patients whose disease had failed to respond to prior CD19-based CAR T-cell treatment. However, outcomes appeared to be improved among patients with higher CD22 antigen density.^10,11 Unfortunately, a multicenter phase II clinical trial closed early partially because of poor clinical outcomes and an increased toxicity signal.

The T-cell immunotherapy obecabtagene autoleucel, recently approved in the treatment of B-cell ALL, uses a unique CD19 binder with a fast binding off rate to improve CAR T-cell engraftment and persistence, which may be particularly important in a disease like B-cell ALL, where B-cell recovery is often a sign of impending relapse.¹² New targets such as BAFF (B-cell–activating factor receptor) are being actively investigated in ongoing CAR T-cell clinical trials (NCT05312801). Further data are needed to know whether the expression level of BAFF impacts clinical response.

What Next for Relapsed B-Cell Malignancies?

The cell therapy field continues to expand with allogeneic CARs under active development, in vivo CARs in early-stage clinical trials, and a multitude of multitargeted or armored CARs being tested in patients with relapsed B-cell malignancies. As the race continues to determine the optimal delivery platform, manufacturing parameters, and targets, it may be time to consider that there may be an ideal CAR design for each B-cell malignancy.

Quick and rapid testing to accurately assess tumor antigens will aid selection of the next best therapy in the current era of targeted therapies. Patients who have B-cell malignancies with a relapsing or remitting course may benefit from a long-lived CAR with prolonged B-cell aplasia to prevent relapse, whereas those with aggressive lymphomas may fare well with a CAR that induces a deep and rapid response but subsequently allows for B-cell recovery, to limit long-term immunosuppression and the subsequent associated infectious risks. Gentler CARs with less toxicity are indicated to improve accessibility of CAR T-cell therapy to our older and frailer patients, whereas a higher-intensity CAR may be acceptable for a younger and fit patient. Such paradigms are no different from our approach to allogeneic stem cell transplant, with both myeloablative and reduced-intensity conditioning regimens.

In conclusion, the future of cell therapy remains bright. In time, we may better understand how to optimize each CAR to the specific disease to maximize clinical outcomes.

DISCLOSURE: Dr. Shah has served as an advisor or consultant to Gilead-Kite, BMS-Juno, Miltenyi Biomedicine, Lilly Oncology, Incyte, AbbVie, Cargo, BeiGene, Kite Pharma, Allogene Therapeutics, AstraZeneca, BMS, Ipsen, Genentech, and Galapagos; has received research funding from Lilly Oncology, Genentech, and Miltenyi Biomedicine; has received travel support from Lilly Oncology and Miltenyi Biomedicine; has served on a scientific advisory board for Tundra Therapeutics; and is a Scholar in Clinical Research for The Leukemia & Lymphoma Society.

REFERENCES

1. Tilly H, Morschhauser F, Sehn LH, et al: Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med 386:351-363, 2022.
2. Tausch E, Schneider C, Stilgenbauer S: Risk-stratification in frontline CLL therapy: Standard of care. Hematology Am Soc Hematol Educ Program 2024:457-466, 2024.
3. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.
4. Hermine O, Hoster E, Walewski J, et al: Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): A randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 388:565-575, 2016.
5. Bhaskar ST, Dholaria B, Savani BN, et al: Overview of approved CAR-T products and utility in clinical practice. Clin Hematol Int 6:93-99, 2024.
6. Majzner RG, Rietberg SP, Sotillo E, et al: Tuning the antigen density requirement for CAR T-cell activity. Cancer Discov 10:702-723, 2020.
7. Plaks V, Rossi JM, Chou J, et al: CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel. Blood 138:1081-1085, 2021.
8. Shah NN, Colina AS, Johnson BD, et al: Phase I/II study of adaptive manufactured lentiviral anti-CD20/anti-CD19 chimeric antigen receptor T cells for relapsed, refractory mantle cell lymphoma. J Clin Oncol. March 31, 2025 (early release online).
9. Le Gouill S, Thieblemont C, Oberic L, et al: Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 377:1250-1260, 2017.
10. Frank MJ, Baird JH, Kramer AM, et al: CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: A dose-finding phase 1 study. Lancet 404:353-363, 2024.
11. Shah NN, Highfill SL, Shalabi H, et al: CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: Updated results from a phase I anti-CD22 CAR T-cell trial. J Clin Oncol 38:1938-1950, 2020.
12. Lamble AJ, Moskop A, Pulsipher MA, et al: INSPIRED Symposium Part 2: Prevention and management of relapse following chimeric antigen receptor T cell therapy for B cell acute lymphoblastic leukemia. Transplant Cell Ther 29:674-684, 2023.

Dr. Shah is Professor of Medicine and Director of the BMT & Cellular Therapy Program at the Medical College of Wisconsin.