Antigen Loss Variants: Catching Hold of Escaping Foes

Abstract

Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

“…This form of acquired resistance can often be attributed to tumor heterogeneity. In the case of immunotherapy, response against specific antigens exerts selective pressure towards antigen-loss cancer cells over time, a concept termed antigen escape [103]. This phenomenon has been observed in patients with triple-negative breast cancer (TNBC) during neoadjuvant chemotherapy (NAC), in which TNBC persisted after treatment in half of the patients.…”

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Among bsAb, bi-specific T cells engagers (BiTEs) and bi-or tri-specific killer engagers (BiKE or TriKE) are dual or triple targeting antibodies, which act by simultaneously binding tumor antigens and effector cells (T cells or NK cells), thus leading to the creation of a new immunological synapse and the triggering of cytotoxic responses. Of note, TriKEs recognize two different antigens on tumor targets allowing the binding of cancer cells even when one antigen is lost, and thus avoiding the occurrence of escape variants [as reviewed in (230)(231)(232)].…”

Development of Spherical Nucleic Acids for Prostate Cancer Immunotherapy

“…This factor may not be significant in human disease, where the clinical observation of prostate cancer often finds slow growth and progression; (4) insufficient impact of targeting a single epitope. Loss of antigen occurs as tumors progress, comprising a mechanism to escape antigen-specific immune responses, one induced by selective pressure ( 48 ). Taken together, our observations in this study provide the basis for designing and optimizing SNAs in future approaches to augment the antitumor T cell immune responses through combination with immune checkpoint blockade therapy (e.g., anti-PD-1/PD-L1) and by raising broad-spectrum T cell immune responses to both MHC class I and MHC class II-restricted antigens simultaneously through multiplexed SNAs that can deliver multiple epitopes.…”