by ecancer reporter Janet Fricker

PV-10, an investigational drug, has demonstrated a reduction of viable melanoma cells in both injected tumours and non-injected bystander tumours, reported a study at the American Association for Cancer Research Annual Meeting, April 5-9, in San Diego, California.

The translational study, which took place concurrently in men and mice, helps to elucidate the immune mechanisms of action of PV-10.

PV-10, a 10% solution of Rose Bengal that was originally used as an agent to stain necrotic tissue in the cornea, has been developed to selectively target and destroy cancer cells without harming surrounding healthy tissue, minimizing the potential for side effects.

Already an open label phase 2 study has demonstrated that injecting cutaneous lesions in Stage III-IV melanoma patients refractory to other treatments produced a best overall response rate judged by modified RECIST (mRECIST) of 51% (26% complete response; 25% partial response).

In the current study investigators led by Shari Pilon-Thomas, Ph.D., and Amod Sarnaik, M.D., from the Moffitt Cancer Center, Tampa, Florida, set out to investigate the mechanism of regression.

The investigators presented data on biopsies sampled from injected tumours and uninjected bystander tumours taken from eight melanoma patients seven to 14 days after PV-10 injection.

The studies showed that immunohistochemical staining of biopsy specimens for mel A (an immunohistochemical marker of melanoma viability) demonstrated the complete disappearance of viable melanoma cells in both the injected and bystander tumours.

The team found that these changes in tumours were accompanied by increased populations of CD3 , CD4 and CD8 T cells along with NKT cells in peripheral blood.

T cells from one patient were purified and went on to exhibit increased interferon-gamma expression when exposed to the patient’s pre-treatment melanoma cells.

“Ironically, the original aim of the trial to assess tumour-infiltrating lymphocytes was thwarted when biopsies of patient tumours collected just seven to 10 days after PV-10 injection no longer contained viable tumour tissue,” said Pilon-Thomas.

In a bilateral murine B16 melanoma model the investigators went on to show that there was a significant increase in the number of dendritic cells (DCs) infiltrating the tumour draining lymph nodes on the same side as the intralesional injection of PV-10.

No change, however, was found in the number of DCs in lymph nodes on the same side as the uninjected tumour.

“These findings suggest that PV-10 treatment leads to the release of DC activating factors,” write the authors.

The investigators additionally showed that PV-10 treatment of B16 tumours in mice led to release of HMGB1, as soluble Damage Associated Molecule Pattern (DAMP), that is known to be important in activation of DCs.

“The study shows that there are plausible immunological processes that explain the bystander response observed in patients. This isn’t a spurious event, it’s a bona fide immunological response,” said Eric Wachter, the Chief Technology Officer at Provectus, who developed the drug.

Studies are now underway in an additional seven patients to take biopsies and blood samples at more frequent time intervals after PV-10 injection to elucidate the pathways more clearly.

References

H Liu, K Kodumudi, A Weber, et al. Induction of anti-melanoma immunity after intralesional ablative therapy. AACR 2014, Abstract number 630.