A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer

Abstract

Checkpoint-blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA-A2 + or -A3 + Stage IIIC-IV CRC patients. Participants were vaccinated weekly with CEA and Her2 peptides plus tetanus peptide and GM-CSF emulsified in Montanide ISA-51 adjuvant for 3 weeks.Adverse events (AEs) were recorded per NIH Common Terminology Criteria for Adverse Events version 3. Immunogenicity was evaluated by interferon-gamma ELISpot assay of in vitro sensitized peripheral blood mononuclear cells and lymphocytes from the sentinel immunized node. Eleven participants were enrolled and treated; one was retrospectively found to be ineligible due to HLA type. All 11 participants were included in AEs and survival analyses, and the 10 eligible participants were evaluated for immunogenicity. All participants reported AEs: 82% were Grade 1-2, most commonly fatigue or injection site reactions. Two participants (18%) experienced treatment-related dose-limiting Grade 3 AEs; both were self-limiting. Immune responses to Her2 or CEA peptides were detected in 70% of participants. Median overall survival (OS) was 16 months; among those enrolled with no evidence of disease (n = 3), median OS was not reached after 10 years of follow-up. These data demonstrate that vaccination with CEA or Her2 peptides is well tolerated and immunogenic. Further study is warranted to assess potential clinical benefits of vaccination in advanced CRC either alone or in combination with CBT.

Peptide-Based Agents for Cancer Treatment: Current Applications and Future Directions

“…The E75 peptide breast cancer vaccine (Her2 p369–p377) [ 153 ] with polyactin A has been demonstrated to increase CD4 + and CD8 + T lymphocytes, enhance splenocyte proliferation, and elevate interferon-γ levels [ 154 ]. Nelipepimut-S (E75, HER2/Neu, NeuVax) (SELLAS Life Sciences, New York, NY, USA) has been tested in clinical trials (NCT00841399 [ 106 ], NCT00091286 [ 107 ], NCT00791037 [ 107 ], NCT01532960 [ 108 ]). However, the Phase III clinical trial (NCT01479244) failed to show the difference in disease-free survival between Nelipepimut-S and placebo [ 109 ].…”

HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target

“…75,76 Several immunogenic HER2/neu peptides recognized by T lymphocytes have been identified to be included in cancer vaccines. This strategy had contrasting preliminary results, 77,78 and further studies are needed to assess the benefits of immune vaccines in mCRC, either alone or in combination with checkpoint inhibitors. [79][80][81] Another attractive approach is adoptive cellular therapy using chimeric antigen receptor T cells, a new class of cellular immunotherapies.…”

Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies

“…In this context, tumor vaccines are needed as an additional immunotherapy option; carcinoembryonic antigen and Her2/neu peptide vaccination has been found to demonstrate immunogenicity in patients with advanced CRC and is well tolerated [ 100 ]. The clinical efficacy of PD-1 blockade has also been demonstrated in HER2-amplified tumors; however, despite the large number of clinical trials and new agents in development, its impact on HER2 amplified breast and gastric cancers is limited [ 101 , 102 ].…”