Chimeric antigen receptor T-cell therapy for the treatment of aggressive B-cell non-Hodgkin lymphomas: efficacy, toxicity, and comparative chimeric antigen receptor products

ABSTRACT

Introduction: Traditionally, outcomes for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma have been poor. There has been a clear need for effective therapeutic options that could produce durable remissions with a reasonable safety profile. The approval of chimeric antigen receptor (CAR) T-cell therapies has been revolutionary in the field because CAR T-cells meet this need for a substantial number of patients. With multiple approved CAR T-cell products and more expected soon, it can be difficult to distinguish between the various products and decide which to use. Effective CAR T-cell therapeutic choice is enhanced by an understanding of the biology of CAR T-cell, as well as the mechanisms associated with both efficacy and toxicity.

Areas Covered: Biology of CAR T-cells, as well as a discussion of their efficacy and toxicity. Mechanisms of resistance, current unanswered questions in the field, issues associated with choosing a CAR T-cell product, and future directions for the advancement of CAR T-cell therapy.

Expert Opinion: Due to differences in study populations and manufacturing times, it is too early to know if there is a ‘best’ choice for CAR T-cell therapy. Decisions must be individualized taking into account patient factors and expected toxicity.

KEYWORDS:

• Chimeric Antigen Receptor (CAR) T-cells
• cytokine release syndrome
• neurotoxicity
• B-cell non-Hodgkin lymphoma

Article highlights

• CAR T-cell therapy has resulted in long-term remissions for approximately 40% of patients with multiply relapsed/refractory aggressive B-cell non-Hodgkin lymphomas. Previously, median overall survival for this population was 6 months; with CAR T-cell therapy, studies have not yet reached median overall survival at more than 2 years of follow up. Thus, anti-CD19 CAR T-cell is a standard of care in the third line for these diseases.

• CAR T-cells combine the specificity and HLA-independence of an antibody molecule with native T-cell machinery and are able to successfully activate and proliferate upon antigen recognition with subsequent tumor cell killing.

• Two current CAR T-cell therapies are currently FDA approved (axicabtagene ciloleucel or axi-cel, tisagenlecleucel or t-cel), with approval of a third product (lisocabtagene maraleucel or liso-cel) expected soon.

• All three of these products are directed against CD19 but differ in their costimulatory domain, which associate with different kinetics of T-cell activation and proliferation.

• Response rates are not affected by traditional high-risk disease factors. Additionally, the degree of magnitude of CD19 positivity does not appear to correlate with response.

• The three products also are associated with different rates of grade 3 toxicity, but because the studies were not entirely simultaneous, management of toxicities has changed over time, and different toxicity scales were used, it is difficult to draw direct comparisons between studies.

• Important mechanisms of resistance include T-cell exhaustion, tumor antigen loss, and the T-cell phenotype of the product itself.

• Analyses of CAR T-cell versus chemotherapy in terms of QALY support that these therapies are cost-effective in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and DLBCL, but these therapies are very expensive and cost containment remains an important goal.

• No one CAR T-cell therapy is clearly best and it is therefore important to familiarize oneself with the published trials and tailor therapy to an individual patient. Clinicians must consider performance status, need for potential bridging therapy, the amount of time that a patient can wait for manufacturing to occur, as well as expected toxicities, when making a determination of which CAR T-cell product to use.

This box summarizes key points contained in the article.

Declaration of interest

CA Jacobson reports the following disclosures: Consulting for Kite, Novartis, Precision Biosciences, Celgene, Pfizer, and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.