Erika J. Crosby, Ph.D. Department of Surgery at Duke University Medical Center and Melinda Telli, MD Medical Oncologist at Stanford University School of Medicine, Department of Medicine discuss SITCS 2020 abstract: 789 Intratumoral plasmid IL-12 expands CD8+ T cells and induces a clinically validated CXCR3 signature in triple-negative breast cancer.
Study
In TNBC, immune checkpoint inhibitors (ICI) have entered the clinical environment but support only a minority of patients. Interleukin-12 (IL-12) is a pro-inflammatory cytokine that is involved in creating the microenvironment of an inflammatory tumor and is essential for effective anti-tumor immune response. Using different delivery routes, it has been studied as an anti-cancer treatment, but intratumoral injection of plasmid IL-12 (tavokinogene telseplasmid; tavo) accompanied by electroporation is a gene therapy strategy with limited immune-related systemic toxicity.
MethodsÂ
Methods These results were then extended to the study of patient samples from a single arm, prospective tavo monotherapy clinical trial (OMS-I140; NCT02531425).
ResultsÂ
Results Further examination of tavo-treated murine tumors resulted in a signature of 50-gene CXCR3 gene expression associated with a reduction in granulocytes, increased antigen presentation, increased infiltration of T cells, and PD-1/PD-L1 induction. A more in-depth look at paired TCR alpha and beta chains on infiltrating tumor T cells (TILs) showed a dramatic change in TIL clonality and post-tavo treatment frequency. Important increases have been observed not only in the number of expanded (>10) clones but also in the robust activation signature lacking in control tumors. Treatment of mice with tavo prior to anti-PD1 therapy resulted in a large proportion of mice having full tumor regression and long-term survival, while none of the mice treated with anti-PD1 alone demonstrated this therapeutic effectiveness. As proof of concept, in patients who demonstrated a greater than 2-fold increase in CD8 TILS by IHC post-treatment, we used nanostring data from OMS-I140 to show a substantial improvement in this signature. In addition, we showed a single patient who had previously been non-responsive to ICI who after participating in OMS-I140, obtained anti-PD1 as their immediate next treatment and demonstrated a substantial clinical response.
ConclusionsÂ
Conclusions Together these data identify a clinically relevant CXCR3-associated gene signature that represents both a potential biomarker for response to ICIs and a potentially targetable pathway for therapeutic intervention in TNBC.