Resistance of Hematological Malignancies and Solid Tumors to CAR T Cell Therapy

Dear Colleagues,

Remarkable clinical responses have been observed in patients with hematological malignancies and solid tumors using modern immune-based approaches such as CAR-redirected adoptive T cell therapy (CAR T cell), which enable autologous T cells to achieve the antigen-specific recognition of tumor cells, activation, and proliferation independent of any major histocompatibility complex. Despite initial success, however, these responses frequently last for a limited time due to the development of resistance. The mechanisms behind CAR T cell-resistance are broad and possibly stem from issues related to tumors and their microenvironment, as well as those related to CAR T cells.

Tumors may have inherent/preexisting resistance to CAR T cell-mediated apoptosis via a variety of mechanisms such as the deregulated expression of Pro/anti-apoptotic proteins, down-regulation/shedding of CAR T cell-specific marker (e.g., CD19), or the constitutive activation of survival signaling pathways (primary resistance). Alternatively, prolonged exposure of sensitive tumors to CAR T cells may result in the development of acquired (secondary) resistance. The selective outgrowth of tumor cells with inherent or acquired resistance that no longer respond to apoptotic stimuli delivered by fully functional CAR T cells will lead to tumor progression and subsequent patient demise.

Alternatively, resistance may be due to issues related to CAR T cells that hinder their anti-tumor efficacy. These include a lack of persistence in the blood stream of patients, inability to transmit the death signals, lack of infiltration into the tumor bed, induction of anergy, and the development of tolerance in the tumor.

Understanding these mechanisms and designing innovative strategies to render tumor cells more receptive to CAR T cell killing could result in improved clinical response rates, reducing the intensity of the conditioning regimen or even the number of infused CAR T cells needed.

This Special Issue will focus on 1: identifying the molecular determinants of inherent or acquired resistance of tumor cells that render them unresponsive to tumor-specific and highly effective CAR T cells, 2: deciphering the mechanisms that render CAR T cells ineffective to eradicate tumor cells, 3: understanding the contribution of the tumor microenvironment in conferring the CAR T cell resistance phenotype to tumors, 4: designing 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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