Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.

The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFβ/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.

Purpose: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. Experimental Design: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. Results: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19⁺, CD19⁻, and mixed CD19⁺/CD19⁻B-cell lymphoma. Conclusions: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.