Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

Abstract

The goal of cancer immunotherapy is to establish new or boost pre-existing anticancer immune responses that eradicate malignant cells while generating immunological memory to prevent disease relapse. Over the past few years, immunomodulatory monoclonal antibodies (mAbs) that block co-inhibitory receptors on immune effectors cells - such as cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) - or their ligands - such as CD274 (best known as PD-L1) - have proven very successful in this sense. As a consequence, many of such immune checkpoint blockers (ICBs) have already entered the clinical practice for various oncological indications. Considerable attention is currently being attracted by a second group of immunomodulatory mAbs, which are conceived to activate co-stimulatory receptors on immune effector cells. Here, we discuss the mechanisms of action of these immunostimulatory mAbs and summarize recent progress in their preclinical and clinical development.

GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

“…In a mouse ovarian tumor model, the combination of GITR ligation and PD1 blockade induced potent antitumor immunity and tumor regression, while anti‐GITR or anti‐PD1 antibodies alone did not have any therapeutic effect . Several clinical studies in cancer patients are currently studying combinatorial targeting of GITR and the PD1/PDL1 pathway . Addition of nivolumab alone enhanced ex vivo TIL responses to a similar extent as GITRL (Supporting Information Fig.…”

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

“…In GBM, CD40/CD40L mRNA expression has been associated with improved survival [41], and antitumor effects have been demonstrated with an anti-CD40 agonistic monoclonal antibody in mouse glioma models [42]. CD137, GITR, and OX40 are also members of the TNF receptor superfamily, and each are immune co-stimulatory receptors expressed on CD4+ and CD8+ T cells, as well as Tregs [43]. Preclinical models have demonstrated efficacy for agonist monoclonal antibodies against CD137 [44], GITR [45], and OX40 [46] in murine glioma, and a clinical trial is currently underway for an anti-CD137 antibody in recurrent GBM (NCT02658981).…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…183,185-187 In several instances, vaccination is further combined with standard treatment regimens including conventional chemotherapy, 117,188-191 radiation therapy, 52,192-195 and targeted anticancer agents, 196-199 or with various immunotherapeutic interventions. 200-205 The latter include (1) immune checkpoint blockers such as the anti-PD-1 mAbs pembrolizumab and nivolumab, 206-208 the anti-PD-L1 mAbs durvalumab and atezolizumab, 209-211 and the anti-CTLA4 mAb ipilimumab; 137,186,212-215 (2) immunostimulatory antibodies such as utomilumab, which stimulates TNF receptor superfamily member 9 (TNFRSF9; best known as 4-1BB or CD137) signaling, 28,216-218 or the CD27 agonist varlilumab; 28,216,219,220 and immunomodulatory agents such as lenalidomide. 221-224 In line with preclinical and clinical data demonstrating that multi-epitope vaccines are generally more powerful than their single-epitope counterparts, 117,225 the most common vaccination strategy employed by these studies consists in targeting simultaneously multiple TAAs (20 studies).…”

“…1-7 Over the past years, a panoply of different approaches has been developed or repurposed to (re)initiate anticancer immunity, 8-12 including immune checkpoint blockers targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) and its main ligand CD274 (best known as PD-L1); 13-19 chemotherapy with immunogenic cell death (ICD) inducers, 20-25 recombinant cytokines, 26,27 monoclonal antibodies (mAbs) that activate co-activatory receptors, 28,29 adoptively transferred T cells engineered to express a tumor-specific chimeric antigen receptor (CAR), 30-36 as well as multiple small molecules targeting distinct immunosuppressive pathways operating within the tumor microenvironment. 37-40 Although some of these strategies have demonstrated unprecedented activity in patients with advanced tumors refractory to several lines of conventional treatment, 41 the fraction of individuals responding to single-agent immunotherapy is generally low, 42-45 arguably with the sole exception of CAR-expressing T cells, which have been associated with >70% overall response rate in pediatric patients with B-cell acute lymphocytic leukemia (ALL).…”