Poten­ti­at­ing Immunother­a­py of Uro­log­i­cal Can­cers with Oncolyti­ic Viruses

Geert­je van der Horst, Mar­jan van de Mer­bel, Thi­js Janssen, Maaike van der Mark, Nadine van Mont­foort, Rob Hoeben, gam­maGabri van der Pluijm

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.

Geert­je van der Horst, Mar­jan van de Mer­bel, Thi­js Janssen, Maaike van der Mark, Nadine van Mont­foort, Rob Hoeben, gam­maGabri van der Pluijm

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.

Potentiating Immunotherapy of Urological Cancers with Oncolytiic Viruses
Potentiating Immunotherapy of Urological Cancers with Oncolytiic Viruses
Potentiating Immunotherapy of Urological Cancers with Oncolytiic Viruses

Gabri van der Pluijm

Gabri van der Plui­jm Ph.D. is Asso­ciate Pro­fes­sor at the Depart­ment of Urol­o­gy, Lei­den Uni­ver­si­ty Med­ical Cen­ter (Lei­den, the Nether­lands) at which he is head­ing the Urol­o­gy Research Lab­o­ra­to­ry. His research is trans­la­tion­al and ranges from 2D and 3D tumour-immune cell co-cul­ture mod­els in vit­ro to pre­clin­i­cal and ‘near-patient’ in vivo dis­ease mod­els for the study of the patho­gen­e­sis of tumour pro­gres­sion and exper­i­men­tal treat­ment of uro­log­i­cal can­cers (prostate, blad­der and renal cancer). 

His group is cur­rent­ly focussing on poten­ti­at­ing cur­rent immunother­a­peu­tic approach­es by oncolyt­ic virus­es and/​or drug repur­pos­ing (can­cer neu­ro-immunol­o­gy), aim­ing at improv­ing the treat­ment out­comes of patients with uro­log­i­cal malig­nan­cies. Dr. van der Plui­jm is (and has been) involved as coör­di­na­tor and prin­ci­pal inves­ti­ga­tor in mul­ti­ple nation­al and inter­na­tion­al research con­sor­tia and research, includ­ing EU-spon­sored Euro­pean Train­ing Net­works. He is tutor of Med­ical and Bio­med­ical Sci­ence students.

More about Asso­ciate Pro­fes­sor Gabri van der Plui­jm.

Gabri van der Plui­jm Ph.D. is Asso­ciate Pro­fes­sor at the Depart­ment of Urol­o­gy, Lei­den Uni­ver­si­ty Med­ical Cen­ter (Lei­den, the Nether­lands) at which he is head­ing the Urol­o­gy Research Lab­o­ra­to­ry. His research is trans­la­tion­al and ranges from 2D and 3D tumour-immune cell co-cul­ture mod­els in vit­ro to pre­clin­i­cal and ‘near-patient’ in vivo dis­ease mod­els for the study of the patho­gen­e­sis of tumour pro­gres­sion and exper­i­men­tal treat­ment of uro­log­i­cal can­cers (prostate, blad­der and renal cancer). 

His group is cur­rent­ly focussing on poten­ti­at­ing cur­rent immunother­a­peu­tic approach­es by oncolyt­ic virus­es and/​or drug repur­pos­ing (can­cer neu­ro-immunol­o­gy), aim­ing at improv­ing the treat­ment out­comes of patients with uro­log­i­cal malig­nan­cies. Dr. van der Plui­jm is (and has been) involved as coör­di­na­tor and prin­ci­pal inves­ti­ga­tor in mul­ti­ple nation­al and inter­na­tion­al research con­sor­tia and research, includ­ing EU-spon­sored Euro­pean Train­ing Net­works. He is tutor of Med­ical and Bio­med­ical Sci­ence students.

Gabriel van der Pluijm | Potentiating Immunotherapy of Urological Cancers with Oncolytic Viruses
Gabri van der Plui­jm, Lei­den Uni­ver­si­ty Med­ical Cen­ter, THE NETHERDLANDS

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