Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens
. 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.
Neoantigens: promising targets for kidney cancer therapy
Commentary by Assoc. Prof. Carlotta Palumbo
Personalised cancer vaccines are emerging as promising targeted-therapies for solid cancers.
Due to the advancement in next-generation sequencing, it is currently possible to identify neoantigens and create personalised neoantigen vaccines, whose effects exclusively apply on tumour cells. Indeed, neoantigens are newly formed antigens generated by tumour cells because of genomic mutations that are recognised as non-self by the immune system. Neoantigens have two unique characteristics: they trigger a strong immune response and since they are absent in normal tissues, the risk of autoimmunity is minimal. Therefore, personalised cancer vaccines (PCVs) against neoantigens offer an interesting opportunity for tumour destruction without hurting healthy tissue and also provide the possibility for long-term protection against tumour recurrence through post-treatment immunological memory.
Recently, the role of PVCs has been explored also in renal cell carcinoma (RCC). Braun et al presented the results of a phase I trial that tested neoantigen-targeting PCVs in patients with high-risk clear cell RCC. The study enrolled nine patients with stage III or IV clear cell RCC who were NED (no evidence of disease) after surgery. Whole exome sequencing and RNA sequencing were performed and personal neoantigens were identified (up to 20 per patients). Based on these neoantigens, peptide-based PCVs were created and then administered to the patient. Five patients received the PCV with ipilimumab subcutaneously administered adjacent to the vaccination site (cohort 1), whereas the other patients received the vaccine alone (cohort 2).
After a median follow-up of 40.2 months after surgery, none of the nine participants enrolled in the study experienced RCC recurrence. The most common adverse events were low-grade injection-site reactions and transient flu-like symptoms. No grade 3 or higher toxicity were reported.
Interestingly, the PCVs were immunogenic in all nine patients. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, vaccination rapidly and durably expanded T cell clonotypes, which persisted years after the last vaccine dose, suggesting a potential pathway of protection against disease recurrence.
Although the findings of this study must be interpreted with caution due to the small sample size, the favourable toxicity profile of PCVs alongside with the durable and persistent immune response highlights the potential beneficial role for these neoantigen-targeting vaccines in RCC. This benefit may be of particular interest in the adjuvant setting, especially in preventing recurrence.