Folate Receptor Alpha Peptide Vaccine Generates Immunity in Breast and Ovarian Cancer Patients

Abstract

Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients. We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later. Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months. The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. .

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

“…27,28 A recent study by Kalli et al indicates that FOLR vaccine may enhance the immune response in patients with breast and ovarian cancers that overexpress FOLR. 29 TROP-2 protein expression was detected in 4 (21%) of 19 cases, with 1 case exhibiting high (2þ / > 50% cells) Trop-2 expression. TROP-2 is a cell-surface receptor that is over-expressed in various carcinomas.…”

Role of Immunotherapy in Triple-Negative Breast Cancer

“…56 Similarly, the folate receptor a vaccine also targets a peptide overexpressed in breast cancer, and led to immune responses that persisted at least 12 months in the initial phase I trial of patients with breast and ovarian cancer. 57 Rather than targeting peptides overexpressed in tumors but also shared by normal cells, neoantigen vaccines target peptides arising from tumor-specific mutations unique to each patient's tumor and not present in normal cells, and therefore T-cell responses to these neoantigens are not limited by self-tolerance. 58 The randomized phase I trial of a neoantigen vaccine with or without durvalumab is enrolling 24 patients with residual TNBC after neoadjuvant therapy (NCT03199040), 59 whereas the randomized phase II trial of nab-paclitaxel and durvalumab with or without a neoantigen vaccine is enrolling 70 patients with treatment-naïve mTNBC who are treated first with gemcitabine and carboplatin for 18 weeks prior to randomization (NCT03606967).…”

Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers

“…TPIV200 is a vaccine targeted toward FRα, and in a phase I study including 14 women with ovarian cancer, the vaccine was safe and elicited or augmented immunity [ 43 ]. As a result, there is an ongoing study comparing TPIV200 with GM-CSF vs. GM-CSF alone as a maintenance therapy after upfront chemotherapy in ovarian cancer (NCT02978222).…”