Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Abstract

1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the promise of combining meaningful efficacy (prolongation of survival) with very good safety and tolerability, as has been shown in several recent randomized trials 1-3 . However, development of cancer vaccines remains a major challenge, with little knowledge of (i) the optimal tumor antigens to target, (ii) suitable agents to counteract regulatory mechanisms opposing successful immunotherapy and (iii) surrogate and predictive biomarkers that can improve our understanding of these regulatory mechanisms and predict a patient's response to therapy. The first major issue addressed in this work is whether relevant HLArestricted peptides for immunotherapeutic intervention in patients with RCC can be identified and clinically validated. We defined the relevance of the antigens as their natural presence on the tumor in the majority of RCC samples, their immunogenicity (induction of T cell responses in clinical studies) and the association of the vaccine-induced T cell responses with clinical benefit. For the identification, selection and preclinical immunological validation of such antigens, we used the antigen discovery platform XPRESIDENT 4,5 to create a multipeptide vaccine designated IMA901 for immunotherapy of RCC. We tested IMA901 in HLA-A*02 + subjects with advanced RCC in two clinical trials, a phase 1 (n = 28) and a randomized phase 2 (n = 68) trial, both of which assessed the association of T cell responses to IMA901 with clinical benefit.

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…Hence, the multi-epitope vaccine targeting driver gene mutations met state-of-the-art requirements for TSA-based vaccines. Most of the latest and more advanced clinical trials for TSA-specific vaccines are based on the administration of Ag cocktails 47,66 . Another recent approach delivers multiple Ags as an individualized neo-antigen mRNA-polytope vaccine 67-69 which represents a promising alternative to administration of antigens via synthetic peptides.…”

“…45 In combinatorial approaches several peptide vaccines have entered phase III clinical trials. 46 Rammensee and colleagues, for example, showed in a phase II trial for metastatic renal cell carcinoma that overall survival was associated with T-cell responses against IMA901 (a multi-epitope peptide vaccine) 47 . This led to a phase III study combining IMA901 with sunitinib (a small molecule receptor tyrosin kinase inhibitor).…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…A large majority of these studies involve either short TAA-derived peptides that can directly bind to MHC Class I or II molecules expressed by antigen-presenting cells 176 (42 studies), or SLPs that are processed intracellularly and then loaded on MHC Class I or II molecules 172,177,178 (22 studies), most often in combination with immunological adjuvants 179-182 like montanide ISA-51 (water-in-oil emulsion) 181,183 Hiltonol® (poly- L -lysine in carboxymethylcellulose, a TLR3 ligand) 184 and GM-CSF. 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.…”

“…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). Alongside, 15 studies are investigating the safety and efficacy of PPV, often consisting of MHC-matched peptides chosen from the immune repertoire of the patient before treatment.…”

“…104-106 Moreover, tumors emerge and evolve as they become able to escape natural immunosurveillance, 107-110 either because the lose expression of potentially antigenic proteins, and/or because they establish an immunosuppressive milieu that enforces local tolerance. 111-116 Thus, besides a few exceptions and despite promising preclinical findings, 117 multiple studies demonstrate that peptide-based vaccines employed as standalone adjuvanted interventions have limited clinical activity (although they generally cause some signs of tumor-targeting immunity). 118-121 In line with this notion, no peptide-based vaccines are currently approved by the US Food and Drug Administration (FDA) or equivalent agencies worldwide for use in cancer patients are therapeutic measures (source http://www.fda.gov).…”