Alternative immune effector cells picking up speed

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Immune effector cell (IEC) therapies are increasingly permeating the landscape of cancer treatment. The main players in this field include genetically modified T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs), natural killer cells, cytotoxic T lymphocytes expanded ex vivo, regulatory T cells with or without genetic modification, and other forms of genetically modified or manipulated effector cells. Preclinical and clinical advances in alternative forms of IECs strive to enhance efficacy and overcome some of the major challenges of IECs such as T cell exhaustion, limited availability of suitable cell-surface antigen targets, and the impact of an immunosuppressive tumor microenvironment. Three emerging approaches were highlighted in a dedicated scientific symposium “Alternative Immune Effector Cells” at the 65th annual meeting of the American Society of Hematology.

Helping CAR T cells stay in the fight

Approaches to enhance CAR T cell persistence can improve overall potency in preclinical models.¹ However, the mechanisms by which CAR T cells durably persist in patients are poorly understood. CAR T efficacy correlates with an enrichment of T cell memory-associated genes,^2,3,4,5,6 thereby implicating memory-associated transcription factors in CAR T cell responsiveness. The Weber group has shown that the transcription factor FOXO1 governs memory programming in human CAR T cells.⁷ Overexpression of FOXO1 enhances stemness, metabolic fitness, in vivo persistence, and antitumor activity in preclinical models. This work provides evidence that memory-associated pathways can be leveraged to enhance CAR T potency.

Advances in TCR-T for hematologic malignancies

The field of TCR-based therapeutics (TCR-T) for solid cancers has steadily advanced over the past two decades and has led to very encouraging results in clinical trials.⁸ TCR-T for hematologic malignancies is also promising, as evidenced by results from clinical trials targeting Wilm’s tumor 1⁹ or preferentially expressed antigen in melanoma.¹⁰ Dr. Bleakley’s team has developed a novel TCR-T targeting the minor histocompatibility antigen HA-1 and is conducting a clinical trial to evaluate HA-1 TCR-T to manage recurrent leukemia after hematopoietic cell transplant. The novel TCR-T construct incorporates a CD8 co-receptor to enable function of the class I-restricted HA-1 TCR in CD4⁺, which then can provide help for CD8⁺ TCR-T.¹¹

Engaging the myeloid compartment for enhancing T cell effector functions

Myeloid cells suppress antitumor immunity and infiltrate the premetastatic niche, driving an immunosuppressive premetastatic gene signature.¹² Poor CAR-T cell expansion has been associated with an expanded myeloid cell compartment characterized by CXCR3-negative classical monocytes, whereas enhanced CAR-T cell expansion has been associated with CXCR3-positive classical and non-classical monocytes, implicating specific myeloid cell populations as either promoting or hindering CAR-T cell expansion.¹³ The Kaplan lab has developed a cell therapy platform termed genetically engineered myeloid cells (GEMys).¹² In preclinical models, GEMys producing interleukin-12 (IL-12) reversed the immunosuppressive premetastatic niche gene signature to initiate an effective T cell-mediated antitumor immune response.¹² An IL-12 GEMy clinical trial based upon this work is under development at the Center for Cancer Research at the National Cancer Institute.

Understanding the molecular mechanisms that enhance IEC potential is essential toward translating these findings into better therapeutic treatments. Importantly, new research data underscore the critical role of the tumor microenvironment in modulating IEC functions, enabling the development of novel therapeutic platforms using and/or targeting this extrinsic regulatory mechanism. As these preclinical data are translated into clinical trials, much promise awaits.