A Review on Immuno-oncology agents for cancer therapy

Abstract

Immuno-oncology (IO) leverages the immune system to attack cancer and has revolutionized therapy across many tumor types [1,2]. Among IO agents, immune checkpoint inhibitors (ICIs) that block CTLA-4 or PD-1/PD-L1 restore cytotoxic Tcell activity [6] and have shown remarkable efficacy in diverse malignancies [1,2]. To date, over a dozen ICIs are FDA-approved for multiple cancer indications, including tissue-agnostic approvals [2].  Adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells (e.g. anti-CD19 or anti-BCMA constructs) have induced high remission rates in hematologic cancers [2].  Therapeutic cancer vaccines aim to prime T-cell responses by delivering tumor-specific antigens to antigen-presenting cells [3].  Despite decades of research, clinical efficacy of cancer vaccines in advanced disease has been modest [3], although prophylactic vaccines (e.g. HPV, HBV) successfully prevent virus-associated cancers. Recent vaccine platforms (e.g. mRNA, dendritic-cell, neoantigen-based) have shown promise, especially in combination with other IO modalities [3]. Oncolytic viruses (OVs) represent another modality: these engineered viruses selectively infect and lyse tumor cells while sparing normal tissues [4]. OVs also release tumor antigens and induce local inflammation, potentially converting immunologically “cold” tumors to “hot” [4]. Talimogene laherparepvec (T-VEC) for melanoma exemplifies OV approval, and many other OVs are in clinical trials [4]. Bispecific Tcell engagers Bispecific T-cell Engagers (BiTEs) are antibody-derived constructs that simultaneously bind a T-cell (via CD3) and a tumor antigen. BiTEs force formation of an immunologic synapse and trigger perforin/granzyme-mediated killing [5]. Blinatumomab (anti-CD19×CD3) was the first FDA-approved Bispecific T-cell Engagers. Bispecific T-cell Engagers (BiTEs) for B-cell acute lymphoblastic leukemia [5]; since then, several others (e.g. CD3×CD20, CD3×BCMA bispecifics) have reached late-stage trials or approval [5]. Despite these advances, IO therapies face significant challenges. Only a minority of patients achieve durable responses, as many tumors evade immunity via suppressive microenvironmental pathways and antigen loss [2]. IO agents can elicit serious immune-related toxicities (autoimmunity, cytokine release syndrome) and incur high cost [1]. Future efforts focus on rational combinations and predictive biomarkers to improve efficacy and safety of IO therapies.

Keywords: immuno-oncology; checkpoint inhibitor; CAR T-cell therapy; cancer vaccine; oncolytic virus; bispecific T-cell engager.