Recent FDA approval of PD-1 therapy for squamous cell carcinoma adds to the existing repertoire of immunomodulatory antibody therapies for cutaneous cancers. Currently, these and other antibody therapies are administered systemically to patients, inducing potent T cell anti-tumour responses. However, their effectiveness can be limited by off target toxicities and variable response rates.
We hypothesized that dose sparing concentrations of combination antibody therapies applied locally to cutaneous tumours may improve the efficacy/safety of existing treatment regimes. To confirm this, we developed a cutaneous TC-1 tumour model by injecting tumour cells into mouse pinnae and injected dose sparing therapies adjacent to growing tumours to test their efficacy. An antibody cocktail consisting of Anti-PD-1/4-1bb/VISTA Abs (10ug/Ab), applied intradermally to tumours, resulted in complete and durable clearance of the tumour. The tumour regression was shown to be T/B cell dependent, and the combination of antibodies was superior to monotherapies delivered intradermally. In contrast, intravenous administration of the same dose of triple antibody therapy failed to induce tumour regression, implying that systemic distribution of the therapy at this dose failed to reach a threshold needed to induce a local, skin anti-tumour response.
Next, we determined if intradermal antibody therapy could have effects beyond the treatment site and induce immune memory. Systemic immune memory was noted when tumour cells applied subcutaneously to the back of mice that cleared an intradermal tumour (30 days previously), failed to develop tumour in contrast to untreated mice. No tumour growth was noted in previously treated and rechallenged animals after 137 days of continued observation. Finally, presence of systemic, tumour antigen specific CD8 cells were confirmed in splenocytes of rechallenged animals.
Taken together, these data highlight the translational potential for potentially safer local delivery of dose sparing concentrations of our unique combination of anti-PD-1/4-1BB/VISTA antibodies to treat cutaneous cancers.