Abstract CT086: H3.3-K27M neoantigen vaccine elicits CD4+ and CD8+ T cells immunity and improved prognosis against diffuse intrinsic pontine glioma
Authors: Zhang Yang , Ji Nan , Chen Gang , Wu Haiyang , Wang Yi , Li Xiao’ou , Xu Wei , Peng Ling , Li Tian , Wang Yi , Zhang Li-Feng , Sun Shengjun , Zhao Xiaobing , Li Si , Alexander Peter , Zhang Liwei , Li Qi-Jing 
Published: April 2023

Background: Diffuse intrinsic pontine glioma (DIPG) harboring H3.3-K27M mutation is a malignant pediatric brain tumor with a &gt;90% mortality rate within two years of diagnosis. Aiming to improve therapeutic outcomes, we herein describe a neoantigen peptide vaccine against H3.3-K27M which effectively triggers both CD8+ and CD4+ T cell responses.

Methods: A neoantigen vaccine was designed to trigger T cell immunity against DIPGs harboring the H3.3-K27M mutation. ENACTING (NCT04749641) was then initiated as an open-label, single center, two-armed phase 1 trial to assess T cell immune responses and vaccine safety. The vaccine was administered intramuscularly with poly-ICLC adjuvant until tumor progression or untolerated toxicity. PBMCs before and after each vaccine treatment were collected for TCR repertoire analysis and immune response assessment.

Results: As of November 2022, 10 patients have been treated. No grade 3-4 treatment-related adverse events have been observed, with fever (80%) and injection site pain (60%) being the most common AEs. On a per patient basis, vaccines induce a landscape change of TCR repertoire in patients’ PBMC after 4-6 times of dosing, indicating multiple dosing is required to trigger extensive T cell responses. T cell responses against neoantigens were detected and H3.3-K27M mutation-specific CD4+ and two CD8+ clones were validated. Among 9 efficacy-assessable patients, the one-year overall survival rate was 71.4%. The mPFS has reached 11.7 months and increasing. One patient reached complete response. As this trial remains ongoing, subgroup analysis will be reported in the future.

Conclusion: The H3.3-K27M neoantigen vaccine was well tolerated and elicited mutation-specific CD4+ and CD8+ T cell responses in patients. Initial results from this ongoing study

suggest that, compared with other current immunotherapies against DIPG, H3.3-K27M peptide vaccination may provide superior patient outcomes, for both life qualities and survival outcomes.

Table 1. Clinical efficacy and adverse events Efficacy Complete response (CR) 1 (11.1%) Partial response (PR) 0 (0) Stable disease (SD) 8 (88.9%) Progressive disease (PD) 0 (0) Disease control rate (DCR) 100% 12-month overall survival 71.4% Median progression-free survival (mPFS) 11.7 months (95% CI, 7.0-NR) Median overall survival (mOS) 15.7 months (95% CI, 10.0-NR) Treatment-Related Adverse Events All grades Grade 3 Grade 4 Fever 9 (90.0%) 0 0 Injection site pain 6 (60.0%) 0 0 Bloating 1 (10.0%) 0 0 Abdominal pain 1 (10.0%) 0 0 Vomiting 1 (10.0%) 0 0 Increased blood LDH 1 (10.0%) 0 0 Proteinuria 1 (10.0%) 0 0 Hypocalcemia 1 (10.0%) 0 0

Citation Format: Yang Zhang, Nan Ji, Gang Chen, Haiyang Wu, Yi Wang, Xiao’ou Li, Wei Xu, Ling Peng, Tian Li, Yi Wang, Li-Feng Zhang, Shengjun Sun, Xiaobing Zhao, Si Li, Peter Alexander, Liwei Zhang, Qi-Jing Li. H3.3-K27M neoantigen vaccine elicits CD4+ and CD8+ T cells immunity and improved prognosis against diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT086.