Allogeneic CAR-T Cells: More than Ease of Access?

Abstract

Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient’s own T cells, disease progression and death prior to return of engineered cells. T cell dysfunction is known to occur in cancer patients, and several groups have recently described differences in CAR-T cells generated from chronic lymphocytic leukaemia (CLL) patients compared with those from a healthy donor. This is thought to contribute to the low response rate in this disease group. Healthy donor, gene-edited CAR-T cells which do not require human leucocyte antigen (HLA) matching have the potential to provide an ‘off the shelf’ product, overcoming the manufacturing difficulties of producing CAR-T cells for each individual patient. They may also provide a more functional, potent product for malignancies such as CLL, where T cell dysfunction is common and frequently cannot be fully reversed during the manufacturing process. Here we review the potential benefits and obstacles for healthy donor, allogeneic CAR-T cells.

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

“…This prolonged manufacturing time can lead to disease progression between leukapheresis and CAR T-cell infusion [37]. The development of allogeneic off-the-shelf CAR T cells with reduced risk of graft-versus-host disease could significantly change the workflow of CAR T-cell therapy if these treatments become available to patients without the requirements for standard CAR T-cell manufacturing [84][85][86][87][88]. Another potential drawback of CAR T-cell therapy is the use of preconditioning lymphodepletion regimens.…”

“…Because these exclusion criteria may limit BCMA-targeted treatment options for these patients, trials assessing anti-BCMA therapies should carefully consider patient selection until we have a greater biological and clinical understanding of how anti-BCMA treatment sequencing may be conducted in the future. For example, patients at high risk of progression may not be suitable for the lag time required for CAR T-cell manufacturing and may be better suited for readily available anti-BCMA products [86]. Further assessment of anti-BCMA therapies in patients with MM with unmet needs (e.g., patients with high-risk MM, elderly and frail patients, or patients with renal failure) is also necessary, as these patients are often excluded from clinical trials [96,97].…”

Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform

“…Several efforts are underway to reduce the cost of CAR-T therapies and make it more scalable. One high priority is to create allogeneic ''universal donor'' cells (Ruella and Kenderian, 2017;Torikai and Cooper, 2016) to provide off-the-shelf cells that can be used for all patients (Graham et al, 2018). To achieve such universal donor cells, the T cell receptor (TCR) complex can be disabled to prevent graft-versus-host disease (Yang et al, 2015) and host-versus-graft elimination can be blocked by mutations within b2-microglobulin that prevent MHC-I surface expression (Ren et al, 2017).…”

Immunotherapy in Multiple Myeloma

“…One of the challenges with this procedure is that the patient's disease might progress during this process and might then not be fit to receive the CAR-T therapy, as it takes time to harvest cells and produce the CARs. There is also a possibility that the number of T cells harvested might not be enough, or are dysfunctional [227]. Recent development has tried to develop 'off the shelf' allogenic CAR-T cell therapies to mitigate these issues.…”