Chapter 11 - Promising Chimeric Antigen Receptors for Non-B-Cell Hematological Malignancies, Pediatric Solid Tumors, and Carcinomas

Abstract

To move beyond the success of CAR T-cell therapy for B-cell malignancy, careful target selection and new mechanisms of engineered T-cell control will be required. Promising targets have been identified, and those currently or soon to be tested in clinical trials will be presented here. Cell surface proteins upregulated on a broad variety of transformed cell types such as NKG2D ligands or CD44 carbohydrate structures are being considered. In hematological malignancy, CD33 and CD123 remain the most promising targets for acute myeloid leukemia. T-cell malignancies do not appear to express leukemia-restricted or non-T cell expressed targets. Nevertheless, engineering CAR T-cells to be free of CD5- or CD7-mediated toxicity has opened new approaches. For pediatric solid tumors, GD2 and CD171 (L1-CAM) have long been of interest, and await improved tumor targeting to demonstrate clinical efficacy. More general targets being evaluated for pediatric solid tumors include HER2, FOLR1/2 (folate receptor), EGFR, CD276 (B7H3), and GPC2. There is strong rationale for each target, and their expression in adult tumors has generated broad interest. Carcinomas have received the greatest benefit from immune checkpoint blockade. However, the sheer number of cases that fail current approaches challenges the field to apply CAR T-cell therapy to broadly expressed carcinoma-associated antigens such as mesothelin, MET, TEM8, MUC1, prostate-specific membrane antigen, prostate stem cell antigen, and GPC3. CAR T-cell-based therapy is also being directed to the immunosuppressive cellular milieu that is part of the solid tumor lesion. Cancer-associated fibroblasts, vasculature, and myeloid- or misdifferentiated marrow-derived cells have each been proposed as CAR targets. Finally, approaches to target cancer stem cell markers such as CD24, CD44v6, and CD133 are being proposed, even while the safety of targeting these antigens has yet to be demonstrated. This wide array of tumor-expressed surface proteins, stem cell markers, and lesion-associated cell types represent an important opportunity for the further development of CAR approaches that directly benefit patients.