Trial Watch

Abstract

Immunostimulatory monoclonal antibodies (mAbs) exert antineoplastic effects by eliciting a novel or reinstating a pre-existing antitumor immune response. Most often, immunostimulatory mAbs activate T lymphocytes or natural killer (NK) cells by inhibiting immunosuppressive receptors, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1), or by engaging co-stimulatory receptors, like CD40, tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40) or TNFRSF18 (best known as GITR). The CTLA4-targeting mAb ipilimumab has been approved by the US Food and Drug Administration for use in patients with unresectable or metastatic melanoma in 2011. The therapeutic profile of ipilimumab other CTLA4-blocking mAbs, such as tremelimumab, is currently being assessed in subjects affected by a large panel of solid neoplasms. In the last few years, promising clinical results have also been obtained with nivolumab, a PD-1-targeting mAb formerly known as BMS-936558. Accordingly, the safety and efficacy of nivolumab and other PD-1-blocking molecules are being actively investigated. Finally, various clinical trials are underway to test the therapeutic potential of OX40- and GITR-activating mAbs. Here, we summarize recent findings on the therapeutic profile of immunostimulatory mAbs and discuss clinical trials that have been launched in the last 14 months to assess the therapeutic profile of these immunotherapeutic agents.

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…40,44,54 Moreover, at least in some cell types, ICD can be provoked by patupilone, an experimental microtubular inhibitor of the epothilone family, [55][56][57] and by 7A7, a monoclonal antibody (mAb) targeting the murine epidermal growth factor receptor (EGFR). 58,59 However, for the reasons mentioned above, FDA-approved epothilones (i.e., ixabepilone, which is licensed for the treatment of breast carcinoma) 60 and EGFR-targeting mAbs (i.e., cetuximab and panitumumab, which are currently employed for the treatment of head and neck cancer and colorectal carcinoma) [61][62][63] may not share this ability with patupilone and 7A7, respectively. Finally, it should be noted that some FDA-approved agents such as digoxin and digitoxin (which are licensed for the treatment of various cardiac disorders), 64 as well as zoledronic acid (which is commonly employed for the treatment of MM or hypercalcemia and bone lesions of oncological origin), 65 are very efficient at boosting the immunogenicity of otherwise non-immunogenic instances of cell death, although they are unable to elicit ICD per se.…”

Trial Watch—Immunostimulation with cytokines in cancer therapy

“…Relatively safe and efficient treatments are indeed available for all the indications mentioned above, perhaps with the single exception of Stage II-III melanoma, which is still treated with surgery followed by IFN-a2b-based immunotherapy. 35,68 Rather, investigators and practitioners are focusing their efforts on the possibility to use recombinant cytokines (at low doses and locally) to boost the anticancer activity of other immunotherapeutic regimens, including checkpoint blockers, [69][70][71][72] adoptive cell transfer, 73-76 oncolytic virotherapy, [77][78][79][80][81] DNA-and peptide-based vaccines, [82][83][84][85][86][87] dendritic cell (DC)-based interventions, [88][89][90][91][92] as well as other immunostimulatory agents like Toll-like receptor (TLR) agonists. [93][94][95][96][97] Here, we discuss recent preclinical and clinical advances in the development of recombinant cytokines for use as immunological adjuvants in cancer patients.…”

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).…”