Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies

Cell-based cancer immunotherapy has revolutionized the treatment of hematological malignancies. Specifically, autologous chimeric antigen receptor-engineered T (CAR-T) cell therapies have received approvals for treating leukemias, lymphomas, and multiple myeloma following unprecedented clinical response rates. A critical barrier to the widespread usage of current CAR-T cell products is their autologous nature, which renders these cellular products patient-selective, costly, and challenging to manufacture. Allogeneic cell products can be scalable and readily administrable but face critical concerns of graft-versus-host disease (GvHD), a life-threatening adverse event in which therapeutic cells attack host tissues, and allorejection, in which host immune cells eliminate therapeutic cells, thereby limiting their antitumor efficacy. In this review, we discuss recent advances in developing stem cell-engineered allogeneic cell therapies that aim to overcome the limitations of current autologous and allogeneic cell therapies, with a special focus on stem cell-engineered conventional αβ T cells, unconventional T (iNKT, MAIT, and γδ T) cells, and natural killer (NK) cells.

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.

Evaluation of Patient Preference and Perception Regarding the Clinical Use of Autologous Versus Allogeneic Cell Therapy in Orthopedic Surgery

Background: Cell therapy has become a hot topic in orthopedics, with significant research dedicated to improving physicians’ understanding of its efficacy. However, little is known about patients’ cell therapy knowledge. Questions/Purposes: The aims of this study were to (1) evaluate patients’ perceptions of cell therapy in orthopedics, (2) determine whether patients have a preference for autologous or allogeneic cell therapy, and (3) assess patient concerns about cell therapy. Methods: Consecutive outpatients of an orthopedic clinic were surveyed from June 2019 to January 2020. All patients were 18 years old or older and being seen for an orthopedic intervention, including rotator cuff repair, anterior cruciate ligament (ACL) reconstruction, arthroscopic meniscectomy, or a cartilage repair procedure such as an osteochondral allograft transplantation or matrix-associated autologous chondrocyte implantation. Results: A total of 50 patients were surveyed (mean age: 53 years). The patients’ average rating for likelihood to use autologous cells was 8.86 ± 2.2 out of 10 and the average rating for likelihood to use allogeneic cells was 6.24 ± 3.3; 46% of patients had no specific concerns about autologous cell therapy, while 28% expressed concerns about efficacy, and 12% had concerns about donor age. The top 2 “main concerns” about allogeneic cell therapy were disease transmission (30%) and immune reaction (24%). Conclusions: This survey found that patients asserted a preference for autologous cell therapy in orthopedics. Further research is necessary to further elucidate the factors related to cell therapy that are most important to patients.