Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy

Abstract

In the landscape of cancer immunotherapy, immune cell engagers (ICEs) are rapidly emerging as a feasible and easy-to-deliver alternative to adoptive cell therapy for the antitumor redirection of immune effector cells. Even if in hematological malignancies this class of new therapeutics already hit the clinic, the development of ICEs in solid tumors still represents a challenge. Considering that ICEs are a rapidly expanding biotechnology in cancer therapy, we designed this review as a primer for clinicians, focusing on the major obstacles for the clinical implementation and the most translatable approaches proposed to overcome the limitations in solid tumors.

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

“…BiTEs demonstrated remarkable efficacy in B cell hematologic malignancies, but the use of such new drugs to treat solid tumors is unsatisfactory [34] . Although BiTEs can redirect T cells to specific tumor antigens and activate T cells directly, the immunosuppressive factors in the TME, including high levels of ROS, hypoxia, TGF-β, etc, are not conducive to the proliferation and survival of T and NK cells in solid tumors, which can importantly reduce its antitumor activity [35,36] . However, the pro-inflammatory cytokine moiety of immunocytokine can convert the tumor immunosuppressive microenvironment to a certain extent, and promotes the activation and proliferation of T and NK cells, which is supported by our results that LH01 can inhibit the apoptosis of CTLL-2 under high levels of ROS and down-regulate the TGF-β1 levels in TME.…”

Humanization of a strategic CD3 epitope enables evaluation of clinical T-cell engagers in a fully immunocompetent in vivo model

“…This novel hCD3E-epi knock-in model offers the opportunity to further evaluate and characterize TCEs in a solid tumor setting leveraging syngeneic tumor cell lines 21 . Some of the challenges associated with the discovery of effective and safe therapies in solid tumor indications include heterogenous expression of the tumor antigen, an immune suppressive tumor microenvironment, and high expression of solid tumor targets in normal tissue leading to off-tumor, on-target toxicities 22 . In this context, TCEs will need to be evaluated in combination with other immunotherapy agents to achieve potent activity 12 , 23 .…”

Research and Clinical Landscape of Bispecific Antibodies for the Treatment of Solid Malignancies

“…Many Fc-free BiTEs are currently under clinical evaluation in solid tumors. For example, catumaxomab, an anti-CD3/EpCAM, was granted European Medical Agency (EMA) approval in 2009 for the intraperitoneal treatment of malignant ascites, but was later withdrawn from the market in 2013 for commercial reasons [ 25 ]. Nonetheless, catumaxomab is currently being investigated for diverse indications in large phase II–III studies ( Table S1 ).…”

“…They work by redirecting immune cells against cancer cells by physically promoting a link between the two, achieving recruitment and activation of immune effector cells. On the immune cell side, ICEs work in a major histocompatibility complex (MHC)-independent manner and utilized, most commonly, CD3 (T cell engagers), followed by CD16 (natural killer, NK, cell engagers) or CD64 (phagocytic cell engagers) [ 25 ].…”