Poten­ti­at­ing Immunother­a­py of Uro­log­i­cal Can­cers with Oncolyti­ic Viruses

Despite the promis­ing effects of immunother­a­py in oth­er sol­id can­cers, prostate can­cer have remained large­ly unre­spon­sive. In blad­der can­cer, immunother­a­py has emerged as a promis­ing ther­a­peu­tic strat­e­gy but not all patients show clin­i­cal­ly-desir­able respons­es to immune-check­point inhibitors.

We hypoth­e­size that oncolyt­ic virus­es (OVs) may unleash the full poten­tial of can­cer immunother­a­py. OVs rep­re­sent a promis­ing ther­a­peu­tic avenue, as OV-treat­ment com­bines tumour cell lysis with acti­va­tion of the immune sys­tem and mount­ing of effec­tive anti-tumour respons­es. For this, we eval­u­at­ed and com­pared the oncolyt­ic and immunos­tim­u­la­to­ry prop­er­ties of mul­ti­ple OVs , i.e. wild­type reovirus (R124) , a spon­ta­neous mutant reovirus (jin‑3) and a new oncolyt­ic deriv­a­tive of the Goril­la-derived Human AdenoVirus‑B (HAdV-lum­c007) ‘GoraVir’ in pre­clin­i­cal, ‘near-patient’ and syn­gene­ic mod­els of prostate and blad­der cancer.

Both reovirus­es vari­ants and GoraVir effec­tive­ly infect­ed and lysed blad­der and prostate can­cer cells in 3D-cul­tures, ex-vivo cul­tured human tumour tis­sue slices and patient-derived xenograft (PDX) mod­els. Notably, jin‑3 par­tic­u­lar­ly, induces a dose-depen­dent expres­sion of immuno­genic cell death mark­ers, inter­fer­on-stim­u­lat­ed genes and inflam­ma­to­ry cytokines. Addi­tion­al­ly, co-cul­tur­ing reovirus- and to a less­er extent GoraVir- infect­ed blad­der and prostate tumouroids with periph­er­al blood mono­cytes result­ed in a sig­nif­i­cant and dose-depen­dent can­cer cell lysis and ele­vat­ed pro­duc­tion of CXCL10 and IFNgam­ma. Admin­is­tra­tion of jin‑3 to immuno­com­pe­tent mice with a sub­cu­ta­neous­ly grow­ing murine prostate can­cer (TRAMP-C2) increased the infil­tra­tion of CD4+ and CD8+ effec­tor cells in the tumour micro-envi­ron­ment result­ing in tumor cell killing and can­cer regres­sion. Tak­en togeth­er, OVs elic­it robust immuno-stim­u­la­to­ry respons­es high­light­ing their poten­tial as anti-tumour agents.