p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy

Abstract

there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced recognition of p53 peptides was detectable after immunization in both the CD4 and CD8 T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4 and CD8 T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. .

Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy

“…Several groups have already shown endogenous T cell reactivity across OvCa patients to various TAA such as mesothelin [47], wild-type or mutated p53 [48][49][50], NY-ESO-1 [51], and Her2/neu [52] among others. However, therapies targeting a particular TAA, either through peptide vaccine or chimeric antigen receptor T cells, have had mixed results due to loss of the target antigen [51] or poor persistence [53] for example.…”

p53, cancer and the immune response

“…Clinical trials of this vaccine in advanced CRC or small cell lung carcinoma patients did not show benefit, despite inducing a p53-specific T cell response (Antonia et al, 2006;Chiappori et al, 2019;van der Burg et al, 2002). However, one phase I trial using MVAp53 gene therapy in platinum-resistant ovarian cancers showed an increase in patient survival (Hardwick et al, 2018). The potential to combine this approach with checkpoint inhibitors remains to be explored.…”

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

“…This circumvents the inhibition of activated, proliferating vaccine-induced T cells, and can dramatically foster T-cell responses by depletion of unwanted myeloid cells [133]. Gemcitabine has been explored in mice and humans in combination DC and other cancer vaccines with promising results [137][138][139][140][141]. Reassuringly, gemcitabine also synergizes with two other types of immune therapy, namely oncolytic virotherapy and ICB [142][143][144].…”