Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications

Abstract

These authors contributed equally to this work. Keywords: ipilimumab, MEDI4736, MPDL3280A, nivolumab, pembrolizumab, urelumab Abbreviations: CRC, colorectal carcinoma; CTLA4, cytotoxic T lymphocyte-associated protein 4; FDA, Food and Drug Administration; IL, interleukin; KIR, killer cell immunoglobulin-like receptor; mAb, monoclonal antibody; NK, natural killer; NSCLC, nonsmall cell lung carcinoma; PD-1, programmed cell death 1; RCC, renal cell carcinoma; TGFb1, transforming growth factor b1; TLR, Toll-like receptor; TNFRSF, tumor necrosis factor receptor superfamily; Treg, regulatory T cellImmunomodulatory monoclonal antibodies (mAbs) differ from their tumor-targeting counterparts because they exert therapeutic effects by directly interacting with soluble or (most often) cellular components of the immune system. Besides holding promise for the treatment of autoimmune and inflammatory disorders, immunomodulatory mAbs have recently been shown to constitute a potent therapeutic weapon against neoplastic conditions. One class of immunomodulatory mAbs operates by inhibiting safeguard systems that are frequently harnessed by cancer cells to establish immunological tolerance, the so-called "immune checkpoints." No less than 3 checkpoint-blocking mAbs have been approved worldwide for use in oncological indications, 2 of which during the past 12 months. These molecules not only mediate single-agent clinical activity in patients affected by specific neoplasms, but also significantly boost the efficacy of several anticancer chemo-, radio-or immunotherapies. Here, we summarize recent advances in the development of checkpoint-blocking mAbs, as well as of immunomodulatory mAbs with distinct mechanisms of action.

Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients

“…In accordance with other studies, we showed that chemotherapy-induced shortterm benefits 27,28 and, in addition with data from clinical trial using immune-based therapies, [29][30][31][32] our results strongly demonstrate that a strong adaptive immune reaction within the tumor is associated with long-term survival for the patients. This could bring some additional evidence to the significant long-term clinical benefits of the immune checkpoint blockade 30,33 or the rituximab treatment, 34 but with contrasted short-term effects. In NSCLC, immunotherapy is a very promising therapeutic approach as reflected by the satisfactory and long-lasting response rates obtained in recent trials targeting the PD1/PD-L1 immunosuppressive pathway.…”

T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

“…10–12 Despite such advances, several challenges exist with use of immune checkpoint agents, including variable response rates in less than half of patients with advanced melanoma (and with even lower efficacy against other cancers deemed ‘less immunogenic’), potential effects on newly discovered immune checkpoint pathways intrinsic to tumor cells, and potential effects on T eff cell homing. 11,13 Importantly, emerging data now implicates defects in T eff cell homing as a critical factor in resistance to immune checkpoint blockade.…”

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

“…25 Notably, the expression of CD274 (a potent immunosuppressive molecule also known as PD-L1) by MDSCs and other immunosuppressive myeloid cells also depends on STAT3. 26 This latter observation suggests that STAT3 inhibition may downregulate PD-L1, implying that combining AZD9150 with checkpoint blockers 27,28 targeting the interaction between PD-L1 and its main receptor (programmed cell death 1, PDCD1, best known as PD-1) may not be useful. However, this conjecture remains to be investigated at the experimental level.…”