T-Cell Engagers in Solid Cancers—Current Landscape and Future Directions

Abstract

Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host’s immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop ‘off-the-shelf’ anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.

Editorial on “Cell Therapy, Bispecific Antibodies and Other Immunotherapies against Cancer”

“…Many different designs of bispecific antibodies are developed with one domain binding to T/NK cells and another domain binding to cancer cell antigens: BITEs, Fc-containing, CrossMab, knob-hole, uni-, bi-valent and others [33,34]. There are several advantages of bi-and tri-specific T cell engagers versus cell therapy, such as off-the-shelf availability, easier logistics of administration and more economical manufacturing [35]. Several challenges exist for this approach, such as toxicity or repressive tumor microenvironment, that will be addressed in future pre-clinical and clinical studies.…”

“…The combination of cell therapy, bi-, tri-specific antibodies, CAR-NK, immunomodulators, checkpoint inhibitors and vaccines will be developed in future pre-clinical and clinical studies [41][42][43]. In addition, a personalized medicine approach will be used when patient tumors are sequenced to detect neoantigens that can be used for dendritic vaccine, bispecific antibody, and cell therapy development [35]. The combination therapy targeting several tumor antigens will be used to better target heterogeneous solid tumors.…”