In recent years, cancer immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy, have shown good efficacy in patients with relapsed/refractory (R/R) hematologic malignancies, where few other options exist. This treatment modality is peculiar in nature, since it is manufactured from living human cells. 1Nevertheless, due to the promising results obtained so far, more than 500 trials are ongoing worldwide. 2
However, this new treatment modality still presents with limitations, and a better understanding of these may lead to improved outcomes for patients. In this article, we will highlight the CAR T-cell therapy limitations and we will review the strategies to overcome them, which emerged during the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) 2020 meetings.
Costs, time between leukapheresis and infusion, and quality of the T cells
Strategies to overcome high product cost include the use of universal CAR (UCAR) T cells, ‘off-the-shelf’ products derived from healthy donor peripheral blood mononuclear cells (PBMCs). 1,3Their manufacturing is easier and allows the treatment of multiple patients from a single manufacturing run, lowering the cost of the drug. In addition, UCAR T cells may represent a valid alternative to the traditional autologous CAR T cells in patients with aggressive disease who need an immediate infusion. The use of UCAR T cells could also improve the quality of T cells, since the cells are from treatment-naïve healthy donors and not from heavily pre-treated patients with a suboptimal memory T cell subset pool. 3
Promising results from the use of allogeneic CAR T cells came from the ALPHA study ( NCT03939026 ) . This phase I, open-label, multicenter, dose-escalation study is the first-in-human study of ALLO-501 plus ALLO-647-based lymphodepletion in R/R diffuse large B cell lymphoma (DLBCL) or follicular lymphoma. The results showed that the treatment was well tolerated, with manageable cytokine release syndrome (CRS) events, and the efficacy was comparable to autologous CAR T-cell products (read the full article here ).
Another option may be treatment in an outpatient setting. The outpatient administration would lower the CAR T-cell therapy cost by reducing expensive hospital stays and would thus make it more accessible. A recent study, evaluating safety and efficacy of lisocabtagene maraleucel (liso-cel; an anti-CD19 autologous CAR T-cell product with a 4-1BB costimulatory domain) following outpatient administration, showed no increase in rates of severe CRS or neurological events (NEs) and similar efficacy rates when compared to inpatient administration (read the full article here ).
Toxicities, such as CRS and neurotoxicities, represent very common adverse events after CAR T-cell infusion. 3An earlier intervention with corticosteroids may help to reduce the incidence of severe CRS and NEs without affecting response rates to CAR T-cell therapy or CAR T-cell expansion. 4A retrospective study, on patients who received licensed CD19 CAR T-cell products between 2019–2020 and developed immune effector cell-associated neurotoxicity syndrome (ICANS) following infusion, showed that corticosteroids-responsive patients had better outcomes compared with corticosteroids-refractory patients. 5
Retreatment with CAR T cells could represent another strategy to attenuate CRS and NEs. In patients (n = 14) retreated with axicabtagene ciloleucel (axi-cel) in the phase I/II ZUMA-1 study ( NCT02348216 ), CAR T-cell expansion, serum cytokine levels, and severe CRS and NEs appear to be attenuated. Because of the limited sample size, further studies with additional patients are needed to confirm these results (watch Frederick Locke discussing the results of this study here ).
To gain more information on the toxicity of CAR T-cell therapy in elderly patients, a retrospective study investigated the toxicity of axi-cel versustisagenlecleucel (tisa-cel) in patients with R/R DLBCL aged ≥70. The use of axi-cel, compared with tisa-cel, was associated with increased toxicities. In addition, a higher cumulative illness rating score (a measure of comorbidities) was associated with more Grade 3/4 CRS and ICANS. 6
In a study recently published in Clinical Cancer Research, Rawan Faramand and colleagues 7identified factors associated with high risk of toxicities in patients with LBCL who were treated with axi-cel. Increased levels of interleukin-6 and an unfavourable tumor microenvironment, prior to CAR T-cell infusion, were associated with a higher risk of neurotoxicity and CRS. Identifying these patients prior CAR T-cell infusion could help with tailored treatment strategies to prevent toxicities in these patients.
Antigen loss, lack of expansion, and persistence
CAR T-cell therapy is a live product that requires special conditions to achieve durable remissions. 1Antigen loss presents a common strategy of tumor cells to escape CAR T-cell attack and could be avoided using dual antigen-targeted CAR T cells. Enhanced expansion and persistence of CARs has been linked with better tumor control and could be improved by introducing new features in the CAR construct, such as novel costimulatory domains and on–off switches, or combining CAR T-cells with other therapies. 1,3
The ALEXANDER study ( NCT03287817 ) ,a single-arm, open-label, multicenter, phase I/II study evaluated the safety and efficacy of the first CD19/22 dual targeting CAR T-cell therapy (AUTO3) in patients with R/R DLBCL. The results, reported here, showed a durable complete response and a favorable safety profile with low levels of CRS and neurotoxicity events. The favorable safety profile may be due to humanized binders, novel spacers, and the costimulatory domains in AUTO3.
Promising preliminary results, with a manageable safety profile and a promising overall efficacy, were also observed in a phase I/IIa clinical trial ( NCT03097770) evaluating the safety and efficacy of tandem CAR T cells targeting CD19 and CD20 in patients with R/R non-Hodgkin lymphoma (read the full article here).
In addition, other factors associated with CAR T-cell expansion, efficacy, and safety may be represented by patient and manufacturing characteristics, such as tumor burden and antigen-specific function of the drug product, as shown in a study on 172 patients with R/R LBCL enrolled in the TRANSCEND NHL 001 study ( NCT02631044 ) andtreated with liso-cel. A higher CAR T-cell expansion was associated with age (p = 0.001), number of prior treatments (p = 0.043), and effector cytokine secretion (p = 0.007). Read the article here.
To date, two CAR T-cell therapies, axi-cel and tisa-cel, have received U.S. Food & Drug Administration (FDA) and European Medicines Agency (EMA) approval for the treatment of some relapsed/refractory (R/R) B-cell malignancies. Both these molecules are second-generation CARs and are specific for CD19. Thanks to the regulatory approval of these first two therapies, the field of CAR T-cell therapy is progressing at a rapid pace, with countless phase I and II trials. The combination of the insights gained from these trials with the input from basic immunology and the advancements in genome engineering will allow refinement of the manufacturing process, lower costs, and improved accessibility.