IMMUNOTHERAPY

Will allogeneic CAR T cells for CD19+ malignancies take autologous CAR T cells ‘off the shelf’?

The question of whether allogeneic chimeric antigen receptor (CAR) T cells could replace autologous CAR T cell therapy has garnered considerable interest, but limited data have been available for comparisons to date. Now, Benjamin et al. have reported their experience with allogeneic anti-CD19 CAR T cells in 21 paediatric and adult patients with acute lymphoblastic leukaemia.

Refers to Benjamin, R. et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet 396, 1885–1894 (2020).

CD19-directed chimeric antigen receptor (CAR) T cells have emerged as a novel and efficacious treatment option for patients with relapsed and/or refractory B cell acute lymphoblastic leukaemia (B-ALL)1 or large B cell lymphomas2, with FDA approvals for ALL and subsequently for lymphoma in 2017. In the period following their FDA approval, adoption of these therapies has increased dramatically in the USA3, as well as in the European Union and in other countries. Importantly, CAR T cells have the potential to be a curative therapy for 30–50% of patients1, depending on the disease and setting. Autologous CAR T cell therapies have presented challenges, however, given that the T cells must be collected and the genetically engineered product manufactured, with full release testing, for each patient. This manufacturing process is expensive and not always successful, with true failure rates of 2–10% in the commercial setting. Allogeneic CAR T cells have the potential to solve many of these problems because they are available ‘off-the-shelf’, can be pre-positioned at the treatment centre or can be supplied without delay, with manufacturing unaffected by patient-specific factors. A cost advantage is also possible, given that multiple doses can be made from a single cell collection and that individual patient release testing is not required. With these benefits in mind, the key question is whether allogeneic CAR T cells will have generally similar efficacy to their autologous counterparts4.

In this regard, Benjamin et al.5 recently reported the initial results of their ongoing multicentre phase I studies of genome-edited, donor-derived, anti-CD19 CAR T cells (UCART19) in 7 children (PALL trial) and 14 adults (CALM trial) with relapsed and/or refractory B-ALL. Patients were required to have CD19+ disease at a morphological (>5% leukaemic blasts in bone marrow) or minimal residual disease (>1×10-3 cells) level. T cells from unrelated healthy donors underwent lentiviral transduction with a CD19/4-1BB/CD3ζ CAR, and transcription activator-like effector nucleases (TALEN) technology was used to disrupt the TRAC (T cell receptor α-chain) and CD52 genes in order to decrease risk of graft-versus-host disease (GVHD) and protect the UCART19 cells from elimination with the lymphodepleting anti-CD52 antibody alemtuzumab, respectively. Following lymphodepletion with fludarabine and cyclophosphamide, with or without alemtuzumab, children enrolled in the PALL trial received UCART19 at a dose of 1.1–2.3 × 106 cells per kg, whereas the adults involved in the CALM dose-escalation trial received 6 × 106, 6–8 × 107 or 1.8–2.4 × 108 UCART19 cells5.

“The results again underscore the ability of CAR T cells to induce remission, even in patients with high disease burden …”

Cytokine-release syndrome (CRS) occurred in 91% of patients overall, and 14% had grade 3 or 4 CRS5. Neurotoxicities occurred in 38% of patients, which were all grade 1 or grade 2. Grade 3−4 cytopenias beyond day 28 occurred in 75% of patients. Two patients experienced grade 1 skin GVHD. Excluding transfusion-associated GVHD as a cause of grade 4 prolonged cytopenias, which were seen in 32% of patients, is difficult. However, prolonged cytopenias can also be seen with autologous CAR T cell products1. Two deaths associated with UCART19 treatment occurred in the CALM trial, one from neutropenic sepsis during grade 4 CRS and the other from pulmonary haemorrhage on day 82 and following allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a patient with persistent cytopenia. The overall response rate was 67%, with 14 patients having complete remission or complete remission with incomplete haematological recovery, and the median duration of response was 4.1 months. Of the 14 responders, 10 proceeded to allo-HSCT. At 6 months, progression-free survival was 27% and overall survival was 55%5.

This important study extends the proof of concept demonstrated in a prior study of UCART19 with two successfully treated infants6. The results again underscore the ability of CAR T cells to induce remission, even in patients with high disease burden (the median bone marrow blast percentage was 8%, but 43% of patients had > 25% blasts)5. Consistent with one of the major advantages of the ‘off the shelf’ approach, 21 patients were enrolled and all 21 were treated with UCART19. In the pivotal ELIANA study of the autologous CAR T cell product tisagenlecleucel in patients with B-ALL, 18% of those enrolled did not undergo cell infusion. The durability of the responses to UCART19 was shorter than that observed in ELIANA (in which the median duration of remission was not reached)1; however, older patients were included in the CALM trial of UCART19 than in ELIANA, in which the maximum age was 25 years. As expected with an allogeneic product, CAR T cell persistence was also shorter: 3 of 21 patients had detectable UCART19 cells beyond day 42 and only 1 had persistence beyond day 120 (ref.5). By contrast, the median persistence of tisagenlecleucel in the blood was 168 days in ELIANA, and in some patients CAR T cells were detectable for up to 20 months1. Like UCART19, the autologous CAR utilized in tisagenlecleucel also contains a 4-1BB co-stimulatory domain, and 83% of patients who responded to tisagenlecleucel in the ELIANA study had maintained B cell aplasia as a functional marker of CAR T cell persistence at 6 months after infusion1. The crucial duration for maintaining CAR T cell persistence is unknown, and might be different in patients with lymphoma than in those with ALL. In patients with ALL, in whom one potential goal of CAR T therapy is the avoidance of allo-HSCT, longer cellular persistence is requisite for a decision not to proceed to allo-HSCT.

“The durability of the responses to UCART19 was shorter than that observed in ELIANA …”

Studies with larger cohorts will be required to gain any sense of whether allogeneic CAR T cell products demonstrate batch-to-batch variability in manufacturing consistency or, more importantly, efficacy. Such products are sourced from healthy donors and have to meet strict release criteria, ensuring some degree of manufacturing comparability; however, insufficient numbers of patients have been treated to date to detect differences in performance. Three batches of UCART19 cell were used in the PALL and CALM studies, and responses occurred in patients treated with each batch5. Indeed, allogeneic CAR T cell manufacturing remains in its infancy. How many doses can consistently be made from a single apheresis product from a healthy donor remains unknown, although a clear limit almost certainly exists. After other factors are optimized, manufacturing techniques intended to increase cell number also increase time in culture, and increased ex vivo culture time can lead to exhaustion and decreased potency of the cells7,8,9.

In comparison with autologous CAR T cells, allogeneic CAR T cells have a barrier to engraftment and proliferation that, at this point, seems to necessitate more intense lymphodepleting chemotherapy. Most experience to date, as illustrated by this report of UCART19 (ref.5) and also by early data from the ALPHA study of a similar allogeneic CAR T cell product (ALLO-501) in patients with lymphoma10, suggests that conventional doses of fludarabine and cyclophosphamide can be used, but use of a lymphodepleting antibody such as alemtuzumab or ALLO-647 (another anti-CD52 antibody) is also necessary to achieve sufficient cell engraftment and proliferation in vivo. Four patients in the CALM and PALL cohorts did not receive alemtuzumab, none of whom had evidence of in vivo UCART19 cell proliferation or an objective response; host lymphocyte recovery also seemed to occur earlier in this group5. Viral reactivation is an important risk associated with alemtuzumab, and was observed in 24% of patients who experienced grade ≥3 viral infections, although none were fatal5.

“A major advantage of the allogeneic approach is the possibility of multiplex gene editing …”

Allogeneic CAR T cells are a class of therapeutics now under rapid development. These agents are being investigated in a variety of haematological malignancies and solid tumours, and a good deal more clinical trial data is likely to be available in the next year or two. However, the UCART19 experience is particularly important because comparisons with autologous CAR T cell products are possible in similar clinical settings. A major advantage of the allogeneic approach is the possibility of multiplex gene editing, where further genetic alterations could improve cellular persistence. Re-infusion of another dose is another possible solution to limited persistence, if there is benefit to having longer persistence, which data from patients with ALL suggest might be the case. The results that emerge over the next 5 years are likely to indicate where the field of CAR T cell therapy is heading in terms of the mix of allogeneic and autologous therapies.

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Correspondence to Stephan A. Grupp.

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S.A.G. has received research support from CRISPR/Vertex, Kite/Gillead, Novartis and Servier, and has been a scientific advisory board or steering committee member and/or consultant for Adaptimmune, Allogene, CBMG, Cabaletta, Cellectis, CRISPR/Vertex, GSK, Janssen/Johnson & Johnson, Juno, Jazz, Novartis, Roche and TCR2. A.D. declares no competing interests.

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DiNofia, A.M., Grupp, S.A. Will allogeneic CAR T cells for CD19+ malignancies take autologous CAR T cells ‘off the shelf’?. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-021-00485-1

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