Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial

Abstract

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

Immunotherapy in Advanced Prostate Cancer—Light at the End of the Tunnel?

“…To date, different peptide vaccines have been evaluated in early phase 1/2 clinical trials, with some thoroughly promising initial results. For example, targeting Ras homolog gene family member C (RhoC) induced a potent and long-lasting T cell immunity in the majority of patients who had previously undergone radical prostatectomy (NCT03199872) [ 110 ]. Additionally, human telomerase reverse transcriptase (hTERT) peptide vaccine UV1 in combination with GM-CSF induced specific immune responses in the majority of mHNPC patients unselected for HLA type with tolerable adverse events [ 111 ].…”

CD4+ T Cells: Multitasking Cells in the Duty of Cancer Immunotherapy

“…Meanwhile, CD4+ T cell activation has evolved as an essential goal of cancer vaccines, whereby two main strategies are used. The first relies on the use of synthetic peptides, either as a mixture of exact MHC-class I and -class II ligands [ 124 , 125 ], or (overlapping) synthetic long peptides (SLPs) [ 126 , 127 , 128 , 129 ]. The second approach uses nucleic acids (DNA or RNA) encoding for the relevant antigens or fragments thereof.…”

“…Although the best anticancer vaccination strategy has not yet been identified (e.g., the vaccine basis, adjuvants or injection scheme), a number of clinical studies have demonstrated that targeting CD4+ T cells is safe. In our experience, antivaccine CD4+ T cell responses are often stronger than CD8+ T cell responses and also last longer, even after vaccination completion [ 128 , 132 ].…”

Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

“…The vaccination with T-cell receptor gamma chain alternate reading frame protein (TARP) and pulsed DCs induced specific immune responses and reduced PSA velocity in D0 PCa patients (NCT00908258) and is currently under evaluation as DCs vaccination in the phase II NCT02362451 study [61]. In a phase I/II trial (NCT03199872), a peptide vaccine against the Ras homolog gene family member C (RhoC) GTPase determined strong CD4+ responses in 18/21 patients after RP [62].…”