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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
A neoantigen vaccine generates antitumour immunity in renal cell carcinoma
David A Braun1,2,3, Giorgia Moranzoni4, Vipheaviny Chea5
1Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. david.braun@yale.edu.
Abstract:
Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.
Insights
Personalized cancer vaccines (PCVs) targeting neoantigens showed high immunogenicity in clear cell renal cell carcinoma (RCC) patients. This approach demonstrated potential as an effective adjuvant therapy, with no recurrences observed in the study cohort.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Personalized cancer vaccines (PCVs) aim to elicit immune responses against patient-specific neoantigens.
- The ability of PCVs to target cancer driver mutations and induce clinical activity, especially in low mutational burden tumors, remains largely unexplored.
- Clear cell renal cell carcinoma (RCC) is a significant malignancy where novel adjuvant therapies are needed.
Purpose of the Study:
- To evaluate the safety and immunogenicity of a neoantigen-targeting PCV in patients with high-risk, resected clear cell renal cell carcinoma (RCC).
- To assess the potential of PCVs to induce T-cell responses against cancer driver mutations and autologous tumors.
- To investigate the clinical activity of PCVs as an adjuvant therapy in RCC.
Main Methods:
- A Phase I clinical trial (NCT02950766) was conducted involving 9 participants with high-risk, fully resected RCC.
- Participants received a neoantigen-targeting PCV, with or without ipilimumab, as adjuvant therapy.
- Immune responses, including T-cell reactivity against PCV antigens and autologous tumors, were assessed, alongside clinical outcomes like recurrence and toxicity.
Main Results:
- No participants experienced recurrence of RCC at a median follow-up of 40.2 months.
- All patients generated T-cell immune responses against PCV antigens, including those targeting RCC driver mutations (VHL, PBRM1, BAP1, KDM5C, PIK3CA).
- Durable expansion of peripheral T-cell clones was observed, and T-cell reactivity against autologous tumors was detected in 7 out of 9 patients. No dose-limiting toxicities were reported.
Conclusions:
- Neoantigen-targeting PCVs are highly immunogenic in high-risk RCC patients.
- These vaccines can effectively target key cancer driver mutations and induce anti-tumor immunity.
- The promising results, including the absence of recurrence, suggest PCVs hold potential as an effective adjuvant therapy for RCC.
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