A groundbreaking clinical trial shows how a personalized cancer vaccine primes the immune system to target kidney cancer, preventing recurrence and offering new hope for patients with high-risk disease.
Study: A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Image Credit: crystal light / Shutterstock
In a recent study published in the journal Nature, researchers demonstrated that a neoantigen-targeting personalized cancer vaccine (PCV) generates anti-tumor immunity in renal cell carcinoma (RCC).
Neoantigens are derived from tumor-specific mutations and are vital targets of anti-tumor immunity. PCVs against neoantigens could potentially induce immune responses to cancer cell-specific epitopes. However, the optimal selection of neoantigen targets and their effectiveness in different cancer types remain areas of active research. PCVs are safe and feasible, capable of eliciting long-term, antigen-specific memory responses in melanoma, which has a high tumor mutational burden and, therefore, many neoantigen targets. However, PCVs face substantial challenges in terms of manufacturing and the induction of immune responses for tumors with a low mutational burden.
RCC is a prevalent disease with a low tumor mutational burden and defined cancer driver mutations. Immune-based therapy could be effective in RCC. However, RCC trials in the adjuvant setting have not demonstrated any clinical benefit. As such, there remains an unmet clinical need to augment outcomes after surgery for high-risk RCC patients, rendering RCC an ideal disease to explore the role of adjuvant PCV treatment.
The study and findings
The present study conducted a phase I clinical trial of PCVs targeting neoantigens in high-risk, resected, clear-cell RCC. Nine patients with presumed high-risk RCC were enrolled, and a PCV was developed and administered. Two patients had metastatic disease, and seven had high-grade disease at enrolment. RCC tumors had about 45 coding mutations per sample. Tumor sequencing was performed to identify the most immunogenic neoantigens, including mutations in key RCC driver genes such as VHL, PBRM1, BAP1, KDM5C, and PIK3CA.
Fifteen peptides containing neoantigens were synthesized, assigned to one of four peptide pools, and administered to each patient as peptide pools. Each patient received ≥ one peptide resulting from a frameshift insertion and deletion. Seven patients received a peptide containing a neoantigen derived from a cancer driver mutation, which was found to be highly immunogenic. Five patients received the vaccine with subcutaneous ipilimumab, while others received PCV alone. Although ipilimumab was well tolerated, it did not significantly impact the magnitude or phenotype of the immune response. However, it did influence antigen-presenting cells at the injection site.
Flu-like symptoms and low-grade injection-site reactions were the common adverse events. No patient had an RCC recurrence after a median of 40 months from surgical resection. One death occurred due to mental health complications and was unrelated to treatment or RCC. PCVs were immunogenic in all subjects. Five patients had vaccine-specific immune responses to all peptide pools.
The highest T cell response ex vivo was observed at 24 weeks post-vaccination in six patients. Moreover, patients exhibited immune reactivity against seven peptides after in vitro stimulation and deconvolution of responses against peptide pools. Importantly, no pre-existing immune responses were detected for any of the vaccine peptides, confirming that all responses were vaccine-induced. The peak magnitude or kinetics of immune responses were not different between ipilimumab recipients and non-recipients.
Most T-cell responses were polyfunctional (i.e., producing ≥ 2 effector cytokines), originated from a cluster of differentiation 4 (CD4) cells, and had a memory phenotype. The peptide containing a mutation in von Hippel–Lindau (VHL), the most common RCC driver gene, was highly immunogenic. Following vaccination, there was a substantial, rapid, and durable expansion of unique T cell clonotypes, which persisted for years after the last vaccine dose. Vaccination also elicited broad, lasting changes in circulating proteins, increasing cytokines and markers of T cell activation and cytotoxicity.
Further, markers of T cell suppression, suppressive myeloid states, and angiogenesis were also amplified. All patients developed inflammatory reactions at injection sites. The team performed biopsies of adjacent sites before (week 0) and after final vaccine priming (week 4). They also performed T cell receptor (TCR) sequencing and single-cell RNA sequencing of infiltrating immune cells from biopsy specimens.
This revealed broad increases in infiltrating lymphoid and myeloid cell populations, with no differences between ipilimumab recipients and non-recipients. Among infiltrating T cells, the overall TCR diversity did not change with vaccination. However, there was an increase in unique T cell clonotypes. The proportion of proliferating natural killer (NK) and cytotoxic T cells among lymphoid cells increased with vaccination. Crucially, PCV-induced T cells demonstrated the ability to recognize autologous tumor cells, highlighting their potential for direct tumor targeting.
Conclusions
In sum, no patient had RCC recurrence after a median of 40 months from surgical resection and 34 months from PCV initiation. Most patients received a PCV against neoantigens derived from cancer driver mutations, which were highly immunogenic. Vaccination resulted in the long-lasting expansion of new T cell clonotypes, suggesting a durable immune response.
Further, vaccination resulted in rapid and durable expansion of T cell clonotypes, persisting years after the last dose. The study demonstrated the feasibility of developing highly immunogenic, neoantigen-targeted PCVs for tumors with low mutational burden. However, because this was a small Phase I study with no control group, direct comparisons to standard adjuvant therapies, such as PD-1 blockade, are not possible. Future randomized controlled trials will be required to assess clinical efficacy. Additionally, scaling up PCV manufacturing and optimizing combination therapies, such as pairing PCVs with immune checkpoint inhibitors, remain key challenges for broader clinical applications.
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