KEY TAKEAWAYS
- The phase 2 trial aimed to investigate the IL-12 expression in TME via IT TAVO-EP + NIVO, correlating immune responses with outcomes.
- Researchers noticed enhanced immune activation post-treatment supports IL12/anti-PD1 efficacy in melanoma.
Intratumoral (IT) TAVO-EP (tavokinogene telseplasmid delivered by electroporation) induces localized IL12 expression in the tumor microenvironment (TME) of melanoma.
A. A. Tarhini and the team aimed to evaluate neoadjuvant (NeoAd) TAVO-EP and NIVO, with patients providing written informed consent (Advarra IRB Pro00041794). Biomarkers of tumoral and systemic immune responses were assessed, correlating with clinical outcomes.
They performed an inclusive analysis of the NeoAd phase, consisting of up to 3 x 4-week cycles of IT TAVO-EP and iv NIVO followed by surgery. Endpoints included pathologic complete response (pCR), near pCR, major response (pMR; pCR + near pCR), and nonresponse (pNR). Biospecimens were collected at screening, C1D8, C2D1 (~30 days from treatment start), and pre-surgery (~90 days).
Slides cut from FFPE tissue underwent chromogenic immunohistochemistry (IHC) for CD8+ tumor-infiltrating lymphocytes (TIL) and PD-L1 (22C3 CDx assay). RNA extracted from FFPE tissue was subjected to NanoString’s IO360 transcriptomic analysis, including Tumor Inflammation Signature (TIS). PBMCs were stained and analyzed via flow cytometry on an LSR Fortessa X-20. Serum samples were analyzed for cytokine levels using the Luminex® MAGPIX® platform (15-plex).
About 16 patients underwent treatment, with 1 showing a partial response but declining surgery and 1 experiencing early distant progressive disease without surgery. Among the 14 who underwent surgery, 2 showed pNR, 3 had near pCR, and 9 achieved pCR, resulting in a pMR rate of 12/15 (80%).
The results revealed that in the tumor at baseline, 9/11 pts tested had <20% CD8+ TIL, 7/11 <10% PD-L1 tumor proportion score (TPS), and 6/10 TIS of ≤0, predicting non-response to anti-PD-1. In 5 pts with evaluable matched tissue at baseline, C2D1 showed that 5/5 had increased peritumoral CD8+ T cells, 4/5 increased CD8+ TIL, 2/5 increased PD-L1, 4/5 increased TIS at C2D1 compared to baseline.
Analysis of the tumoral transcriptome profile revealed significant upregulation of genes associated with innate and adaptive immune responses (IFN-gamma, APM, granzymes, CD8, PD-L1, JAK1, chemokines, others) at C2D1. In blood, proliferating Ki-67+/PD-1+/CD8+ T cells expanded at C2D1, while total PD1+/CD8+cells decreased.
The decrease of PD1+CD8+ cells and other subtypes in blood at C2D1 coincided with TME infiltration by CD8+ cells. Serum effector cytokines, including IL12, IFN-gamma, and IL2, showed no biologically meaningful changes following treatment or differences between responders and non-responders.
The study concluded that most patients exhibited low levels of CD8+ TIL, PD-L1 expression, and TIS at baseline. However, treatment led to enhanced immune activation in both the tumor microenvironment (TME) and blood, characterized by increased immune-related gene expression, CD8+ TIL, peritumoral CD8+ T cells, and TIS. Demonstrating efficacy, 4/5 patients with negative predictive baseline biomarkers for CD8+TIL/PD-L1/TIS low experienced pCRs.
The study was sponsored by the H. Lee Moffitt Cancer Center and Research Institute.
Source: https://www.abstractsonline.com/pp8/#!/20272/presentation/7443
Clinical Trial: https://clinicaltrials.gov/study/NCT04526730
Tarhini A. A., Eroglu Z., Zager J. S., et al. (2024). “Tumoral and systemic immune modulation with neoadjuvant (NeoAd) intratumoral (IT) TAVO-EP (plasmid IL-12 electro gene transfer) and nivolumab (NIVO) in patients (pts) with operable locoregionally advanced melanoma.” Presented at AACR 2024 (Abstract 3734 / 20).
