Cancer Vaccines in Phase II/III Clinical Trials: State of the Art and Future Perspectives

Abstract

The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…A multi-center phase II clinical trial using gp100 peptide with or without IL-2 shows that the gp100 peptide vaccine plus IL-2 group had a significant improvement in centrally verified overall clinical response as compared with the IL-2-only group (16% vs 6%), as well as longer progression-free survival [185]. MAGE-A3 peptide/protein vaccines were also tested in phases II and III clinical trials [186][187][188], but a MAGE-A3 phase III clinical trial failed to meet the projected requirement in patients with resected nonsmall cell lung cancer. Consistent with these clinical development of cancer vaccines, phase I trials using NY-ESO-1 recombinant protein or synthetic peptides have been conducted in melanoma and ovarian cancer patients [189][190][191][192], showing that NY-ESO-1 vaccines can induce antigen-specific immune responses, but are insufficient to eradicate cancer cells.…”

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…Generally, phase I and some phase II clinical trials are performed on patients with advanced disease and after administration of multiple chemotherapy regimens, thus with severe immune-impairment [2]. In heavy tumor-burden patients, the ability of vaccines to generate anti-tumor immune response is strongly limited by numerous tumor-produced immunosuppressive factors (eg, transforming growth factor-β and vascular endothelial growth factor) and immunoregulatory mechanisms (eg, regulatory T cells [Tregs] and myeloid derived suppressor cells) [5].…”

“…Presently, CVs can probably have an important role as adjuvant to traditional therapies in the management of minimal residual disease, in particular for patients who are at high risk to relapse [2]. In this context, a recent randomized phase III study reported by Schuster et al [14] suggests that it would be possible to identify a subgroup of patients with follicular lymphoma in first remission after standard treatment, who may benefit from receiving an anti-Id vaccination [15].…”

“…Several reasons may explain the limited clinical success of anti-tumor vaccination, including the trial design, the specific vaccination approach and host-related factors [2]. One of the main limitations is due to the impaired interplay between tumor and host immune system, which involves the selection of highly aggressive transformed cells that no longer express cancer-specific molecules, the induction of immune tolerance mechanisms (for example the down-regulation of the antigen-processing machinery, the production of immunosuppressive cytokines, the lack of co-stimulatory molecules) and the recruitment of tolerizing dendritic cells and Tregs, which negatively contrast the immune response [2].One of the main drawbacks of CVs is also the functional dissociation between systemic and local immune responses. This is mainly linked to the lack of reliable immunologic surrogate INTRODUCTION______________________________________________________________ 8 markers of clinical response.…”

“…Antibody production has been reported to correlate with clinical outcome only in some cases [7,8], while findings regarding the diagnostic significance of T-cell responses are conflicting. Some papers claimed indeed that no currently available in vitro assays can accurately mirror the in vivo antitumor activity of T-cells [2], whilst others were able to show a clear correlation between clinical outcome and tumor-specific T-cell responses in the peripheral blood [10][11][12][13].Presently, CVs can probably have an important role as adjuvant to traditional therapies in the management of minimal residual disease, in particular for patients who are at high risk to relapse [2]. In this context, a recent randomized phase III study reported by Schuster et al [14] suggests that it would be possible to identify a subgroup of patients with follicular lymphoma in first remission after standard treatment, who may benefit from receiving an anti-Id vaccination [15].…”