Resistance of Hematological Malignancies to CAR T Cell Therapy
A special issue of Cells (ISSN 2073-4409).
Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 2878
Special Issue Editor
Interests: immunotherapy; NHL; ALL; apoptosis; signal transduction; adoptive cell therapy; resistance
Special Issues, Collections and Topics in MDPI journals
Special Issue Information
Dear Colleagues,
Remarkable clinical responses have been observed in patients with hematological malignancies such as non-Hodgkin’s lymphoma (NHL), Acute Lymphoblastic Leukemia (ALL), and Multiple Myeloma (MM) using modern immune-based approaches such as CD19CAR redirected adoptive T cell therapy (CAR T cell). Chimeric antigen receptors (CARs) bestow autologous T cells with antigen-specific recognition of tumor cells, activation, and proliferation independent of the major histocompatibility complex. Engineered T cell therapy (CAR and T cell receptor (TCR) engineered T lymphocytes) has shown increasing promise in clinical investigations at multiple institutions across the nation and abroad. Considerable effort has been dedicated to effector cell production (e.g., high transduction rates) and the intensity of the conditioning regimen; much less attention has been paid to the tumor and its microenvironment. It is well-established that cytotoxic T cells kill tumor targets via non-receptor (perforin/granzyme) and receptor-mediated (TNFa/TNF-R1, TNF-R2, TRAIL/TRAIL receptors (DR4, DR5, DcR1, DcR2), and Fas (CD95)/FasL (CD95L)) apoptotic signal transduction pathways. In turn, tumors may have inherent/preexisting resistance to apoptotic death signals through a variety of mechanisms. Alternatively, tumors may develop resistance to engineered T cells upon successful initial therapy, resulting in tumor recurrence or relapse. This is due to altered dynamics of the expression profile of pro- and anti-apoptotic proteins (due to deregulation/constitutive hyper-activation of various signal transduction pathways such as NF-kB, JAK/STAT, MAPK, AKT/ PKB, etc.) favoring an anti-apoptotic tumor milieu.
Although very effective, innovative strategies are needed to improve CD19CAR T cell therapy, both in responding patients and in instances where tumors may have varying degrees of preexisting or acquired resistance to T cell-delivered apoptotic death signals. Understanding these mechanisms and obtaining strategies to render tumor cells more receptive to T cell killing could result in better response rates, reducing the intensity of the conditioning regimen or even the number of infused CAR T cells needed. This Special Issue focuses on the inherent or acquired resistance mechanisms of tumor cells which render them unresponsive to tumor-specific and highly effective CAR T cells and the design of novel strategies to render tumors sensitive to apoptotic death signals delivered by CAR T cells, thus creating a proapoptotic tumor microenvironment (immune-sensitization).
Dr. Ali R. Jazirehi
Guest Editor
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Keywords
- NHL
- ALL
- CAR T cell
- immunotherapy
- resistance
- apoptosis
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