"Off-The-Shelf" allogeneic chimeric antigen receptor T-cell therapy for B-cell malignancies: current clinical evidence and challenges.

Chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment landscape for hematologic malignancies, notably B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL). While autologous CAR T products have shown remarkable efficacy, their complex logistics, lengthy manufacturing process, and high costs impede widespread accessibility and pose therapeutic challenge especially for patients in rapid need for therapy. "Off-the-shelf" allogeneic CAR T-cell therapy (alloCAR T) has emerged as a promising alternative therapy, albeit experimental to date. AlloCARTs are derived from healthy donors, manufactured by batches and stored, making them available off-the-shelf which lowers financial burden. Various gene editing techniques have been employed to mitigate graft-versus-host disease (GVHD) and host-versus-graft (HvG) to enhance alloCAR T persistence. In this review, we summarize available manufacturing techniques, current evidence, and discuss challenges faced with the use of alloCAR Ts.

Engineering NK-CAR.19 cells with the IL-15/IL-15Rα complex improved proliferation and anti-tumor effect in vivo.

Introduction: Natural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into clinical applications. Adoptive transfer of CAR-NK-92 cells holds out the promise of therapeutic benefit at a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, it has not achieved breakthrough clinical results yet, and further improvement of CAR-NK-92 cells is necessary. Methods: In this study, we conducted a comparative analysis between CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) with IL-15/IL-15Rα (CAR.19-IL15/IL15Rα) to promote NK cell proliferation, activation, and cytotoxic activity against B-cell leukemia. CAR constructs were cloned into lentiviral vector and transduced into NK-92 cell line. Potency of CAR-NK cells were assessed against CD19-expressing cell lines NALM-6 or Raji in vitro and in vivo in a murine model. Tumor burden was measured by bioluminescence. Results: We demonstrated that a fourth- generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model. Conclusion: Together with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15Rα comprising fourth-generation CARs may overcome the limitations of NK-92 cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals.

Differences in the Development of Adverse Infusion Reactions to Rituximab in Patients With Systemic Lupus Erythematosus, Rheumatoid Arthritis and Non-Hodgkin's Lymphoma-Enigma Variations.

It has become clear that rituximab treatment is useful for both B-cell malignancies and autoimmune rheumatic diseases. However this treatment is associated with an increased risk of an allergic reaction. We have reviewed the frequency with which these reactions occur in these different conditions. They appear to be less frequent when rituximab is used to treat rheumatoid arthritis and systemic lupus perhaps because concomitant steroids are invariably given to these patients with the rituximab which is not necessarily the case with the treatment of B-cell malignancies.

Characterization of selective and potent PI3Kδ inhibitor (PI3KDIN- 015) for B-Cell malignances.

PI3Kδ is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate anti-proliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.