1468 Evaluation of safety and immunogenicity of a melanoma vaccine, with or without a systemic agonistic CD27 antibody (CDX-1127), in patients with stage II-IV melanoma

<h3>Background</h3> Agonistic antibodies to costimulatory molecules can enhance activation and survival of T cells. In a phase I trial, an agonistic antibody to CD27 (CDX-1127) was safe and bioactive and decreased regulatory T cells (Tregs).¹ We report results of a randomized phase I/II trial of a vaccine of six class II MHC-restricted melanoma peptides (6MHP)² plus CDX-1127. We hypothesized that the combination would be safe, would decrease Tregs and enhance 6MHP immune responses and memory. <h3>Methods</h3> Adult participants with high-risk stage IIA-IV melanoma were enrolled at two centers (target enrollment 30). All received 6MHP vaccine (200 mcg each) emulsified in an incomplete Freund’s adjuvant + polyICLC on days (d)1, 8, 15, 36, 57, 78 plus a booster (without pICLC) on d176. Participants were randomized 1:1 to receive (Arm A) or not (Arm B) CDX-1127 (3mg/kg body weight) intravenously every 5 weeks x 3. Primary endpoints were toxicity (CTCAE v5) and immunogenicity (direct IFNγ ELIspot assay), including assessment of a memory boost after the d176 vaccine. T regs were assessed by flow cytometry. <h3>Results</h3> Thirty-three eligible participants (54% males) were enrolled and treated. After enrolling 12 participants, DLTs for Arm B (vaccine alone) crossed the DLT threshold, leading to study hold and revision, after which no DLT thresholds were crossed. Most AEs were Grade 1- 2, but eight participants (24%) experienced Grade 3 treatment-related AEs. DLTs (grade 2–3) occurred in 1/17 (6%) on Arm A and 5/16 (31%) on arm B, including vaccine site reactions (4), pneumonitis (1), and visual changes (1). The DLT on arm A was a vaccine site ulceration, considered related to vaccine but not to CDX-1127. CD4⁺ T cell responses to 6MHP were detected ex vivo in 64% and 69% on arms A and B, respectively. Of 15 evaluable, 71% and 50% had memory boost responses for Arms A and B, respectively (figure 1). Regulatory T cells were reduced dramatically (mean &gt;80%) for Arm A (figure 2A), with a lesser decrease in total lymphocytes (40%) (figure 2B). <h3>Conclusions</h3> Adding CDX-1127 to a melanoma helper peptide vaccine was safe and well-tolerated, and induced durable decreases in regulatory T cells. There was no impact on overall T cell response rate, but a trend to greater memory recall at 6 months. CDX-1127 may be useful for reducing regulatory T cells at this dose and schedule, and these data enable powering a larger study to test for enhancement of T cell memory. <h3>Trial Registration</h3> NCT03617328. <h3>References</h3> Infante JR, Burris HA, Ansell SM, Nemunaitis JJ, Weiss GR, Villalobos VM, Sikic BI, Taylor MH, Northfelt DW, Carson WE, Pilja L, Hawthorne TR, Davis TA, Yellin MJ, Keler T, Bullock T. Immunologic activity of an activating anti-CD27 antibody (CDX-1127) in patients with solid tumors. <i>J Clin Oncol</i>. 2014;<b>32</b>(5s):abstract 3027. Slingluff CL, Petroni GR, Olson W, Czarkowski AR, Grosh WW, Smolkin M, Chianese-Bullock KA, PY N, Deacon DH, Nail CJ, Merrill P, Fink R, Rehm PK. Helper T cell responses and clinical activity of a melanoma vaccine with multiple peptides from MAGE and melanocytic differentiation antigens. <i>Journal of Clinical Oncology</i>. 2008;<b>26</b>(30):4973–80. doi: 10.1200/JCO.2008.17.3161. PubMed PMID: 18809608; PMCID: PMC2652084. <h3>Ethics Approval</h3> The study was performed with ethics approval from the University of Virginia Health Sciences Research Institutional Review Board (HSR-IRB; #20085), which served as the central IRB for both sites. The other site (Virginia Commonwealth University) has a reliance agreement in place with their IRB. This trial was also performed under FDA review (IND # 10825) All participants give written informed consent before participating in the study.