Immunotherapy for pancreatic cancer: A 2020 update.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poorer outcomes compared to other breast cancer subtypes. Contributing to the worse prognosis in TNBC is the higher rates of relapse and rapid progression after relapse. Advances in targeted therapeutics and conventional chemotherapy for TNBC have been stymied due to the lack of specific targets. Moreover, the responses to chemotherapy in TNBC lack durability, partially accounting for the higher rates of relapse. Immunotherapy, notably immune-checkpoint blockade, has shown to improve survival and maintain robust antitumor responses in both hematologic and solid malignancies. Unlike lung cancer, melanoma, and bladder cancer, most breast cancers are not inherently immunogenic and typically have low T cell infiltration. However, among breast cancer subtypes, TNBC is characterized by greater tumor immune infiltrate and higher degree of stromal and intratumoral tumor-infiltrating lymphocytes (TILs), a predictive marker for responses to immunotherapy. Moreover, in TNBC, the high number of stromal TILs is predictive of more favorable survival outcomes and response to chemotherapy. Immunotherapy is being extensively explored in TNBC and clinical trials are showing some promising results. This article focuses on the rationale for immunotherapy in TNBC, to explore and discuss preclinical data, results from early clinical trials, and to summarize some ongoing trials. We will also discuss the potential application of immunotherapy in TNBC from a clinician's perspective.

https://www.dovepress.com/getfile.php?fileID=46838

The clinical promise of immunotherapy in triple-negative breast cancer.

Considering the high importance of immune surveillance and immune escape in the evolution of cancer, the development of immunotherapeutic strategies has become a major field of research in recent decades. The considerable therapeutic breakthrough observed when targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the induction and proper activation of an immune response against cancer. In this context, therapeutic vaccination, which can induce a specific immune response against tumor antigens, is an important approach to consider. However, this strategy has its advantages and limits. Considering its low clinical efficacy, approaches combining therapeutic cancer vaccine strategies with other immunotherapies or targeted therapies have been emphasized. This review will list different cancer vaccines, with an emphasis on their targets. We highlight the results and limits of vaccine strategies and then describe strategies that combine therapeutic vaccines and antiangiogenic therapies or immune checkpoint blockade. Antiangiogenic therapies and immune checkpoint blockade are of proven clinical efficacy for some indications, but are limited by toxicity and the development of resistance. Their combination with therapeutic vaccines could be a way to improve therapeutic outcome by specifically stimulating the immune system and considering a global approach to tumor microenvironment remodeling.

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Therapeutic Cancer Vaccine and Combinations With Antiangiogenic Therapies and Immune Checkpoint Blockade

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We demonstrate the construction of a vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we use this vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. We show that mice immunized with these sMVA vectors develop robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

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Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform.

Cancer vaccines: the next immunotherapy frontier

Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

A heavily pretreated patient with triple negative breast cancer distinguished by cutaneous metastases received p53MVA vaccine in combination with pembrolizumab. Her cutaneous metastases regressed and after 2 cycles of therapy, a skin biopsy showed a complete pathological response. Systemic response was confirmed with restaging CT and bone scans. Activation of p53-specific T cell responses and elevation of multiple immune response genes in peripheral blood correlated with the rapid clinical response which lasted for 6 months after the initiation of combined therapy.

Complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53MVA vaccine with pembrolizumab

206Background: Mutations in the p53 gene are present in a majority of solid tumors, resulting in the accumulation of oncogenic and potentially immunogenic p53 protein within tumor cells. We have developed a genetically engineered Modified Vaccinia Ankara (MVA) virus to express wild type p53 transgene (p53MVA) as an immunotherapeutic strategy. We observed robust p53-specific CD8+ T cell responses which were further enhanced by anti-PD-1 treatment. This phase 1 study evaluates the safety and tolerability of the p53MVA vaccine in combination with pembrolizumab. Methods: Patients with non-small cell lung, head and neck squamous cell (HNSCC), hepatocellular (HCC), renal cell, melanoma, bladder, soft tissue sarcoma, triple-negative breast (TNBC), pancreatic (PDAC) and MSI high colorectal cancer failing or intolerant to standard treatment were eligible. Confirmation of p53 involvement by immunohistochemistry or mutational analysis was required for eligibility. A 3-at-risk rolling design was employed and patients...

Kathryn Zurcher

Papers

Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

Complete regression of cutaneous metastases with systemic immune response in a patient with triple negative breast cancer receiving p53MVA vaccine with pembrolizumab

A phase 1 study of p53MVA vaccine in combination with pembrolizumab.