Widespread access to CAR T-cell therapy remains a problem, and quite a few challenges have arisen in regards to optimizing outcomes for CAR T-cell therapy in patients with hematologic malignancies and solid tumors.
Cellular therapy is a form of immunotherapy whereby human immune cells are engineered, expanded, and then infused into patients with cancer.1 Chimeric antigen receptor (CAR) T-cell therapy has revolutionized management of hematologic malignancies, but questions remain. Widespread access to CAR T-cell therapy remains a problem, and quite a few challenges have arisen in regards to optimizing outcomes for CAR T-cell therapy in patients with hematologic malignancies and solid tumors.
CAR T-cell therapy is difficult to obtain, not just for individual patients; many institutions and cancer treatment centers have limited access to CAR T-cell therapy as a modality. In the US, smaller institutions may not be able to obtain manufacturing slots for commercial CAR T-cell therapy and lack the resources and the access necessary to open industry sponsored cell therapy clinical trials. It follows that lack of close proximity to a treatment center and costs of travel may limit patient access as well. Of critical importance in the US, racial minorities are underrepresented in cohorts treated with commercial CAR T-cell therapy and in clinical trials. On a global scale, large areas of the world cannot afford the high costs of producing CAR T cells. That being said, solutions to these problems may be closer than we think.
Place of care (POC) manufacturing of CAR T cells is an exciting and rapidly growing field that holds the potential to address these challenges. POC manufacturing, compared with the commercial centralized manufacturing model, can provide faster production times. Clinical trials using a POC manufacturing approach have resulted in reduced vein-to-vein times, potentially reduced costs, maintained clinical efficacy, and excellent manufacturing success rates.2,3 Shorter manufacturing time can also increase production capacity, which is desirable particularly in the early phases of product release when production slots are limited and turnaround time isn’t optimal.4 POC manufacturing also allows for centers with decreased access to commercial products to provide CAR T-cell therapy to their own patients. Finally, POC manufacturing supports the study of novel manufacturing practices and has the potential to improve translation of novel products from bench to the bedside.
The use of allogeneic CAR T (allo-CAR T) cells which have been engineered to mitigate the risk for graft-vs-host disease are another promising avenue to improve access and cost. Allo-CAR T cells offer the potential for an off-the-shelf living drug that could be universally used, bypassing difficulties with complicated cell collection and processing requirements. A challenge to allo-CAR T-cell efficacy is reduced CAR T-cell persistence due to recipient immune rejection; however, multiple clinical trials are ongoing with a focus on editing techniques to improve persistence and activity of off-the-shelf allo-CAR T-cell products.
Despite unprecedented successes, failure after CAR T-cell therapy for diffuse large B-cell lymphoma still occurs in up to 70% of patients.5,6 One mechanism of failure results from host-patient-disease interactions, namely, the immunosuppressive tumor microenvironment (TME). The immunosuppressive effect of the TME in patients with systemic inflammation and/or high disease burden can reduce expansion of CAR T cells and increase exhaustion.7 Novel regimens to abrogate TME-mediated CAR T-cell inhibition are being studied. They include immunomodulatory agents, radiation therapy, and novel bridging or conditioning regimens done pre–CAR T-cell therapy.8,9 Additionally, early initiation of salvage and/or consolidative immunomodulatory therapies post CAR T-cell therapy can decrease TME effect on CAR T-cell function and improve outcomes.
We have yet to make major advances in terms of CAR T-cell therapy for patients with solid tumors, and to date there are no FDA-approved agents. Clinical trials for CAR T-cell agents in solid tumors have been characterized by relatively low efficacy and increased toxicity compared with CAR T-cell agents used for hematologic malignancies.10 CAR T-cell therapy is ideal for tumors with targets that are ubiquitously expressed with relatively low expression on normal tissue. Solid tumors are highly heterogenous, and many antigen targets are present on normal tissue. Because of that, finding optimal targets has been problematic.10 Also, solid tumors contain a highly robust and immunosuppressive TME that impairs trafficking to and function of CAR T cells within the tumor.11 Novel preconditioning regimens, T-cell receptor engineered T-cell therapy, and natural-killer cell therapies represent promising strategies that may address some of the difficulties experienced in the solid tumor realm.
1. Gonzales Carazas MM, Pinto JA, Casado FL. Biological bases of cancer immunotherapy. Expert Rev Mol Med. 2021;23:e3. doi:10.1017/erm.2021.5
2. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569-1575. doi:10.1038/s41591-020-1081-3
3. Castella M, Caballero-Baños M, Ortiz-Maldonado V, et al. Point-of-care CAR T-cell production (ARI-0001) using a closed semi-automatic bioreactor: experience from an academic phase I clinical trial. Front Immunol. 2020;11:482. doi:10.3389/fimmu.2020.00482
4. Tyagarajan S, Spencer T, Smith J. Optimizing CAR-T cell manufacturing processes during pivotal clinical trials. Mol Ther Methods Clin Dev. 2019;16:136-144. doi:10.1016/j.omtm.2019.11.018
5. Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol. 2020;38(27):3095-3106. doi:10.1200/JCO.19.02103
6. Pasquini MC, Hu ZH, Curran K, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414-5424. doi:10.1182/bloodadvances.2020003092
7. Locke FL, Rossi JM, Neelapu SS, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898-4911. doi:10.1182/bloodadvances.2020002394
8. Gauthier J, Bezerra ED, Hirayama AV, et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021;137(3):323-335. doi:10.1182/blood.2020006770
9. Fang PQ, Gunther JR, Wu SY, et al. Radiation and CAR T-cell therapy in lymphoma: future frontiers and potential opportunities for synergy. Front Oncol. 2021;11:648655. doi:10.3389/fonc.2021.648655
10. The Lancet Oncology. CAR T-cell therapy for solid tumours. Lancet Oncol. 2021;22(7):893. doi:10.1016/S1470-2045(21)00353-3
11. Wagner J, Wickman E, DeRenzo C, Gottschalk S. CAR T cell therapy for solid tumors: bright future or dark reality? Mol Ther. 2020;28(11):2320-2339. doi:10.1016/j.ymthe.2020.09.015