Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation.

BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation. METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor. RESULTS: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ubmut) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor. CONCLUSIONS: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation.

A Rare Adrenal Incidentaloma That Mimics Adrenocortical Carcinoma.

OBJECTIVE: We present a case of an adrenal hemangioma, an uncommon cause of an adrenal mass, and review the clinical presentation, work-up, and management of adrenal incidentalomas. BACKGROUND: A 64-year-old male was found to have a right adrenal incidentaloma during work-up for elevated liver transaminase levels, later found to be from hepatitis C. The mass was suspicious for adrenocortical carcinoma on CT imaging. Biochemical evaluation revealed no evidence of function. He underwent an open right adrenalectomy. The mass was found to be an adrenal hemangioma on histopathologic analysis. METHODS: This is a case report with pertinent review of the diagnosis and management of adrenal incidentalomas. RESULTS: Adrenal hemangiomas are rare, benign, nonfunctional tumors typically found during imaging for other reasons. As illustrated by this case, they appear similar to adrenocortical carcinoma on CT imaging. The diagnosis is usually not made prior to surgical resection. CONCLUSION: Adrenal hemangioma is a rare nonfunctional adrenal incidentaloma that displays atypical features on CT imaging. The suspicion for adrenocortical carcinoma usually prompts adrenalectomy.

Development of an adenovirus vector vaccine platform for targeting dendritic cells.

Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber-fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber-fibritin-sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber-fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets.

Mammaglobin-A is a target for breast cancer vaccination.

We recently completed a phase 1 clinical trial demonstrating the safety of a mammaglobin-A DNA vaccine in patients with metastatic breast cancer. We are currently enrolling patients with early stage breast cancer in a phase 1b clinical trial. The mammaglobin-A DNA vaccine will be administered concurrently with neoadjuvant endocrine therapy, providing a unique opportunity to examine the impact of vaccination in the tumor microenvironment.