Moving a Carbohydrate Mimetic Peptide into the clinic

Abstract

Tumor-Associated Carbohydrate Antigens (TACAs) are broad-spectrum targets for immunotherapy. Immunization with Carbohydrate Mimetic Peptides (CMPs) is a strategy to induce broad-spectrum TACA-reactive antibodies hypothesized to interfere with cellular pathways involved in tumor cell survival. A Phase I study was conducted with a first-in-man CMP referred to as P10s, conjugated to the Pan T cell carrier PADRE, along with MONTANIDE(™) ISA 51 VG as adjuvant over a course of 5 immunizations. While designed as a safety and tolerability study, the potential for therapeutic impact was observed in a subject with metastatic lesions as evaluated before and after vaccine treatment. The subject received Vinorelbine and Trastuzumab (VT) for two months prior to study eligibility. PET scans showed partial response in the lungs and complete resolution of a previously enlarged subpectoral lymph node. Immunization with P10s vaccine resulted in responses to P10s, with serum and plasma antibodies reactive with and cytotoxic to human breast cancer cells in vitro, including the Trastuzumab-resistant HCC1954 cell line. However, the patient developed cystic masses in the brain parenchyma with no apparent evidence of metastases. The subject was switched to Docetaxel, Pertuzumab and Trastuzumab a year later, and her last PET scan showed a complete response in the lungs and lymph nodes. Incubation of cancer cells with a combination of vaccine-induced serum and docetaxel suggests that the induced antibodies sensitize tumor cells for more efficient killing upon administration of docetaxel. The data suggest that P10s-PADRE induces anti-tumor antibody response that in combination with chemotherapy can affect metastatic lesions in breast cancer patients.

Antibodies at the Center of Immunotherapy: Commentary on “Moving a Carbohydrate Mimetic Peptide into the Clinic”

“…The ability of these antibodies to bind to TACA and interfere with signalling events also suggest additive or synergistic modality with chemotherapeutics that are cytotoxic. Most importantly, our studies suggested a potential clinical benefit to the combination of TACA-reactive antibodies as illustrated by the multiple antibodies induced with the P10s vaccine in cancer patients [1]. The sensitization of cancer cell via inhibition of cell survival pathways, show for the first time that signalling pathways interrupted by vaccine induced TACA reactive antibodies causes tumor regression in combination with standard of care chemotherapeutics.…”

“…Our observation that P10s immunization enhances reactivity to the ganglioside GD2 and LeY in humans is one example of inducing responses to multiple TACAs with a pan-immunogen, which has therapeutic ramifications such as driving epitope spreading. In our early phase clinical trial we observed some direct clinical benefit in one of our subjects with metastatic lesions as evaluated before and after vaccine treatment [1]. Inducing antibodies to multiple TACA can contribute to overcome immune-escape mechanisms since TACA are always expressed on tumor cells which increases the therapeutic potential of this cancer vaccine.…”

“…Instead of targeting the tumor itself, as in conventional cancer therapies, activating and mobilizing the immune system to attack its "abnormal self " necessitates the training of the immune system to see a collection of antigens expressed on tumor cells. We have recently shown that a novel immunogen can recruit antibodies to breast cancer tumors that can inhibit tumor cell growth [1]. These vaccine-induced antibodies are cross-reactive with Tumor Associated Carbohydrate Antigens (TACA), which are intimately involved in cell survival signaling.…”

“…We have shown that CMPs induce anti-tumor-reactive humoral [26][27][28] and cellular responses [29,30]. We have moved one of these CMPs, with the sequence WRYTAPVHLGDG (referred to as P10s) conjugated to the Pan-T-cell epitope PADRE, into an early-phase clinical trial in Stage IV breast-cancer subjects [1]. This CMP was designed to mimic and induce responses to TACAs that are associated with glycolipid moieties including the ganglioside GD2 and the LeY [28,31].…”

Targeting tumor-associated carbohydrate antigens: a phase I study of a carbohydrate mimetic-peptide vaccine in stage IV breast cancer subjects

“…MCF-7 cells are known to have a dysfunctional caspase 3, [ 36 ] and a lack of growth-inhibitory activity could be due to caspase-3 deficiency in this cell line. Our previously published data [ 37 ], through testing for Annexin V-FITC/PI on serum-treated MDA-MB-231 cells, implicated apoptosis in P10s-induced antibody-mediated growth inhibition. If the induction of apoptosis is caspase-3-dependent, then apoptotic antibodies do not affect cells deficient in caspase-3 activity.…”