Discussion
death, DLTs, tumor, melanoma, Melanoma, hyper-stimulation, toxicity, SD, CRS, infection, hepatitis
TUMOR, VIRUS, LIVER METASTASES, MELANOMA, MELANOMA, DISEASE, METASTASES, INFECTION, SECONDARY, HEPATITIS
Our study evaluated VSV-IFNβ-TYRP1 given via IT and IV administration in a previously treated population of patients with MUM. Treatment was generally well tolerated with 1 patient experiencing DLTs at DL4, which resolved in 14 days. DLTs included: decreased platelets (grade 3), increased AST (grade 3), and CRS (grade 3). CRS criteria was met due to organ toxicity seen as grade 3 hepatitis. For our primary endpoint of safety, VSV-IFNβ-TYRP1 highlights that a VSV-IFNβ OV can be safely administered concurrently with IT injection and IV administration if the correct precautions are taken. A prior study of VSV-IFNβ (NCT01628640) resulted in a patient death after IT injection, which is thought to be due to extensive liver metastases. This prompted our study to limit enrollment to patients with a tumor burden in the liver of 25% or less. Additionally, incorporation of TYRP1 may focus the immune response more in the tumor, and less in off-target sites, while also improving T cell immunity. Combining IT and IV administration has not been previously investigated. In theory, this approach allows for direct introduction of the OV to the tumor to initiate a UM-specific immune response while the IV dose allows for a systemic exposure of the OV to other metastases. The robust anti-viral responses and emergence of T cell responses to melanoma antigens seen here lends support to this hypothesis. However, we recognize that biodistribution of IV therapies tends to be limited by dilution in systemic circulation and sequestration by the reticuloendothelial system (While there were no clear objective responses to VSV-IFNβ-TYRP1, efficacy was a secondary endpoint. However, we did find dose-dependent immunogenicity to virus encoded TYRP1, with more responses at DL 3 and 4 compared to DL 1 and 2 (Induced Immune Response to Melanoma Antigens.2 patients (6 and 7) treated with ICIs after the trial experienced clinical benefit, seen as stable disease (SD) for 22 and 36 weeks, respectively. These patients showed clear T cell reactivity against both virus encoded TYRP1 and other melanoma associated antigens (gp100, hTERT, cyclin D1), which suggests increased immunogenicity after VSV-IFNβ-TYRP1.As well as an empty vector for re-stimulation of T cells, we used the SIINFEKL peptide from ovalbumin (which is a known H2Kb-restricted murine epitope) as a negative control for stimulation of T cells. Since this is a known epitope in the C57Bl/6 murine system, we reasoned that this would form a negative control to identify any background T cell reactivity against an irrelevant peptide which could be induced by the presence of generalized T cell stimulation by VSV, an effect we have observed in some pre-clinical studies. In this respect, we did observe small but significant increases in T cell reactivity to this non-specific SIINFEK stimulator in 3 patients at DLs 2 and 3, indicating hyper-stimulation of T cells by VSV infection. Interestingly, at DLs 3 and 4 we also observed T cell reactivity against hTERT and, at all dose levels, against Cyclin D1. Given the evidence of a possible VSV-associated enhanced T cell reactivity against SIINFEKL, it is difficult to interpret the significance of the responses to hTERT or Cyclin D1 as they might reflect epitope spreading against possible tumor associated antigens.Finally, as expected, we observed robust anti-VSV T cell responses in the majority of patients treated with the virus (In our pre-clinical melanoma models, we observed that anti-PD1 therapy administered concomitantly with VSV virotherapy significantly decreased anti-tumor T cell responses (as measured by IL-12 levels). In contrast, when anti-PD1 therapy is administered sequentially to viral injection, anti-tumor immune T cell responses increase (While T-VEC is the only FDA approved OV to date, as of 2020 there have been 30 trials performed investigating OVs in melanoma (Looking forward, we propose combining OVs, such as VSV-IFNβ-TYRP1, with both additional target antigens to avoid the chances of antigen escape, as well as with other immunomodulatory treatments given the evidence of epitope spreading observed (Overall, VSV-IFNβ-TYRP1 is safe when given via IT injection and IV administration in patients who have less than 25% tumor burden in the liver. While there were no clear objective responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to melanoma antigens was seen, both to virus-encoded TYRP1 and other melanoma antigens (gp100, hTERT, and cyclin D1), suggesting epitope spreading. Subsequent ICI therapy led to sustained responses for 2 patients, whom both showed evidence of epitope spreading on T cell 