A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

Patrick M Dillon, Gina R Petroni, Mark E Smolkin, David R Brenin, Kimberly A Chianese-Bullock, Kelly T Smith, Walter C Olson, Ibrahim S Fanous, Carmel J Nail, Christiana M Brenin, Emily H Hall, Craig L Slingluff Jr, Patrick M Dillon, Gina R Petroni, Mark E Smolkin, David R Brenin, Kimberly A Chianese-Bullock, Kelly T Smith, Walter C Olson, Ibrahim S Fanous, Carmel J Nail, Christiana M Brenin, Emily H Hall, Craig L Slingluff Jr

Abstract

Background: Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial.

Methods: A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays.

Results: Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series.

Conclusions: Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination.

Trial registration: ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://ichgcp.net/clinical-trials-registry/NCT01532960.

Keywords: Breast cancer; TLR3; agonist; cancer vaccine; cytotoxic T-cell lymphocyte response; immunotherapy; peptide; poly-ICLC.

Conflict of interest statement

Ethics approval and consent to participate

All patients provided written informed consent. The protocol was approved by the institutional review boards or ethics committees of the University of Virginia. The study was conducted in accordance with declaration of Helsinki with good clinical practice as defined by the International Conference on Harmonization.

Consent for publication

Not applicable.

Competing interests

Dr. Slingluff serves as an external advisor for Immatics, and as PI for the MAVIS vaccine trial run by Polynoma. UVA receives funds from those roles. Dr. Slingluff receives licensing payments for patents on peptides used in vaccines, but not for ones in this vaccine. Dr. Dillon has received research funding on behalf of his institution from Merck Pharmaceuticals, Novartis Pharmaceuticals, Eli Lilly and Company, and Pfizer Pharmaceuticals.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Schema. The general schema of treatment including the timing of the vaccine series and the times for blood draws for ELIspot analysis is shown
Fig. 2
Fig. 2
Stimulated ELIspot responses. Four confirmed responses and 2 near-responders to the multi-peptide vaccine following in vitro stimulated and analyzed by ELIspot. The x-axis shows both the week of study and the vaccine number (v = 1, etc). The y axis is label for the adjusted ratio of spots to negative control. The dashed line indicates the preferred threshold ratio for response and is set at a threshold ratio of 2.0 and minimum of 20 T cells per 100,000 CD8+ T cells in a stimulated assay. Only the HLA relevant peptides for each patient are shown. *In all graphs there is at least one peptide (marked *) for which the adjusted ELIspot ratio remained 0 throughout and the corresponding data points for ratio of 0 are not shown

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