KEY TAKEAWAYS
- The phase 1 trial aimed to investigate the immunogenicity of atezolizumab and PGV-001 combination therapy in patients with UC.
- Researchers noticed that vaccination with personalized neoantigens alongside anti-PD-L1 induces T-cell responses in UC, warranting larger trials for a comprehensive assessment; further investigation is ongoing.
Urothelial cancer (UC), primarily originating from the bladder, presents significant therapeutic challenges. Immune checkpoint inhibitors (CBIs) demonstrate enduring responses in select UC patients, suggesting a deficiency in neoantigen-primed T cells.
Mansi Saxena and the team aimed to assess the safety and immunogenicity of atezolizumab and PGV-001, a personalized genomic neoantigen vaccine, in combination therapy.
Researchers performed an inclusive analysis within this phase I trial, enrolling UC patients for PGV-001 administration with atezolizumab in either the adjuvant (after radical cystectomy or nephroureterectomy with high recurrence risk) or metastatic setting. Each PGV001 vaccine comprised up to 10 neoantigen synthetic long peptides (SLPs) predicted using the OpenVax pipeline.
Subjects received 10 PGV-001 vaccines and 1200 mg i.v. atezolizumab every 3 weeks for up to 12 months (adjuvant) or 24 months (metastatic). To investigate T cell immunity, ex vivo IFNγ ELISPOT and T cell expansion assays utilized 15mer overlapping peptide (OLP) pools corresponding to each neoantigen SLP.
The results revealed that in the ex vivo ELISPOT analysis of samples from 9 subjects (3 adjuvant, 6 metastatic), at least 1 neoantigen elicited an immune response in 100% of cases. Among 87 evaluated neoantigens, 47% were immunogenic, showing an average 16.7-fold increase in ex vivo ELISPOT response over baseline. In the adjuvant cohort, 39% (11/28) of peptides were immunogenic, compared to 51% (39/50) in the metastatic cohort, though statistical significance couldn’t be determined.
T cell expansion assays for 6 subjects (3 adjuvant, 3 metastatic) suggested that 46% and 54% of peptides induced CD8+ and CD4+ T cell responses, respectively. A higher proportion of neoantigens induced CD8+ and CD4+ T cell responses in the metastatic setting. Epitope mapping for 5 evaluable subjects analyzed 141 OLPs, with a similar number found to be immunogenic for CD8+ (31.2%, 44/141) and CD4+ (30%, 43/141) responses.
The study concluded that vaccination with personalized neoantigens alongside systemic anti-PD-L1 induces neoantigen-focused T-cell responses in adjuvant and metastatic disease settings. However, the single-arm trial design and limited sample size hinder the definitive assessment of combination therapy components. Future studies will explore the efficacy of this approach on a larger scale, incorporating pre- and on-treatment analyses of treatment-driven immunomodulation.
The trial was sponsored by Matthew Galsky.
Source: https://www.abstractsonline.com/pp8/#!/20272/presentation/10579
Clinical Trial: https://clinicaltrials.gov/study/NCT03359239
Saxena M, Anker J, Kodysh J, et al. (2024). “Immunogenicity of Atezolizumab plus personalized neoantigen vaccination (PGV-001) in patients with urothelial cancer in adjuvant vs metastatic setting.” Presented at AACR 2024 (Abstract LB113 / 1).
