Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

Abstract

Elimination of cancer cells through anti-tumor immunity has been a long-sought after goal since Sir F. Macfarlane Burnet postulated the theory of immune surveillance against tumors in the 1950s. Finally, the use of immunotherapeutics against established cancer is becoming a reality in the past 5 years. Most notable are the monoclonal antibodies directed against inhibitory T cell receptors cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1). The next generation of monoclonal antibodies targeting T cells are designed to stimulate co-stimulatory receptors on T cells. Here we review the recent progress on these immunostimulatory agonist antibodies against the costimulatory receptors CD137, GITR, OX40, and CD27.

Trial watch: STING agonists in cancer therapy

“…112 Corroborating initial findings, the intratumoral or systemic administration of DMXAA or other STING agonists, alone or combined with other therapeutic agents, have ultimately been attributed pronounced therapeutic effects in numerous murine models of fibrosarcoma, glioma, 80 melanoma, 66,113 as well as breast, 114-117 colorectal 118 and prostate carcinoma. 119 Moreover, various CDNs have been shown to boost the therapeutic activity of anticancer vaccines in a variety of tumor models, including (1) mouse 4T1 triple-negative mammary carcinomas treated with a Listeria monocytogenes-based vaccine; [120][121][122] (2) mouse B16 melanomas treated with the TRIVAX vaccine, which consists of synthetic peptides, the Tolllike receptor 3 (TLR3) agonist polyinosinic:polycytidylic acid (polyI:C) 123 and co-stimulatory antibodies 124,125 targeting CD40, 126 or the STINGVAX vaccine, a cellular vaccine engineered to secrete colony-stimulating factor 2 (CSF2, best known as GM-CSF), 127 plus an immune checkpoint blocker targeting programmed cell death 1 (PDCD1, best known as PD-1), [128][129][130] and (3) mouse CT26 colorectal carcinoma treated with the STINGVAX vaccine plus a PD-1 blocker. 128,130 However, natural CDNs are rapidly degraded by circulating and cell-bound enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 131 calling for the development of molecules with improved stability for clinical applications.…”

T-cell agonists in cancer immunotherapy

“…In particular, the use of a single agonist drug has shown a lack of response in early-phase trials, and the overall response to these agonists is, contrary to researchers' expectations, very low (less than 10%). 101 However, when combined with other treatment methods, synergism has been observed. Overall, a deeper understanding of the impact of these agents in vivo is needed to help identify logical combination approaches that can be tested in the clinic Regarding subtypes of cancers, patients treated with urelumab with nivolumab and MK-4166 with pembrolizumab in melanoma patients have had overall response rates of more than 50%.…”

Regulation of CD137 expression through K‐Ras signaling in pancreatic cancer cells

“…Although the role of CD137 has been intensively studied in immune cells [27], its expression and function in cancer cells are still poorly understood. CD137 expression has been detected in lung tumor [18], leukemia [19], and lymphoma cells [20].…”

“…The expression of CD137 in immune cells and its normal biological functions have been well characterized, and CD137 agonists have been tested as anticancer agents [27]. However, the cancer-related biological functions of CD137 remain unclear.…”