Back­ground: The gut micro­bio­me mod­u­lates host immu­ni­ty and respons­es to immune check­point inhibitors (ICIs) in can­cers such as non-small cell lung can­cer (NSCLC). Fecal micro­bio­ta trans­plan­ta­tion (FMT) from ICI-respon­sive donors can improve out­comes in ICI-refrac­to­ry patients, but FMT-based approach­es suf­fer from donor avail­abil­i­ty, com­po­si­tion­al vari­abil­i­ty, safe­ty issues, and lim­it­ed scal­a­bil­i­ty. KAN-001 is a ful­ly defined, Live Bio­ther­a­peu­tic Prod­uct (LBP) com­prised of dozens of strains and designed to reca­pit­u­late the ben­e­fi­cial prop­er­ties of respon­der FMT while offer­ing a con­sis­tent and scal­able man­u­fac­tur­ing process sup­port­ed by strain-lev­el assays. Impor­tant­ly, the strains com­pris­ing the prod­uct were iso­lat­ed from a can­cer patient who obtained a com­plete response to PD‑1 ther­a­py, and whose FMT was able to elic­it response in can­cer patients with tumors ini­tial­ly refrac­to­ry to ICI. We report pre­clin­i­cal effi­ca­cy, strain engraft­ment data, and process devel­op­ment high­lights sup­port­ing the planned clin­i­cal eval­u­a­tion of KAN-001. 

Meth­ods: KAN-001 can­di­dates were eval­u­at­ed in the MCA205 murine tumor mod­el in com­bi­na­tion with anti-PD‑1 ther­a­py. Com­par­a­tive arms includ­ed treat­ment with FMT from ICI-non-respon­der donors. Engraft­ment of KAN-001 strains was assessed in vivo by metage­nom­ic sequenc­ing and HiPR-FISH, a high-plex imag­ing approach that enables spa­tial map­ping of strain col­o­niza­tion in host tis­sue. The use of the HiPR-FISH plat­form also enabled the opti­miza­tion of KAN-001 can­di­dates, includ­ing strain addi­tions through HiPR-ID – based tar­get­ed iso­la­tion. Run-to-run man­u­fac­tur­ing con­sis­ten­cy was assessed using small-scale pro­duc­tion runs ana­lyzed by metage­nomics and HiPR-Vie, a HiPR-FISH – based plat­form allow­ing strain-lev­el via­bil­i­ty pro­fil­ing of com­plex micro­bial communities. 

Results: KAN-001 com­bined with ICI treat­ment result­ed in tumor vol­ume regres­sion supe­ri­or to FMT from ICI-non-respon­der donors, with opti­mized can­di­dates lever­ag­ing HiPR-FISH show­ing improved tumor con­trol in the murine mod­el. Metage­nom­ic pro­fil­ing con­firmed repro­ducible in vivo engraft­ment of KAN-001 strains, with HiPR-FISH reveal­ing spa­tial­ly dis­tinct col­o­niza­tion pat­terns across the GI tract. Man­u­fac­tur­ing process devel­op­ment runs demon­strat­ed con­sis­tent strain abun­dance across repli­cates, and HiPR-Vie analy­sis con­firmed viable rep­re­sen­ta­tion of all strains across runs. 

Con­clu­sions: KAN-001 is a ratio­nal­ly designed, defined LBP that enhances ICI response in mul­ti­ple pre­clin­i­cal mouse mod­els and exhibits robust man­u­fac­tur­ing and ana­lyt­i­cal tractabil­i­ty. A Phase 1 clin­i­cal tri­al is planned in NSCLC patients with both ICI naïve and refrac­to­ry cohorts. Pri­ma­ry end­points will include safe­ty and tol­er­a­bil­i­ty, with sec­ondary assess­ments of engraft­ment and pre­lim­i­nary effi­ca­cy. KAN-001 will be admin­is­tered oral­ly in an encap­su­lat­ed frozen liq­uid for­mu­la­tion with induc­tion and main­te­nance dos­ing. Micro­bio­me pro­fil­ing will be per­formed through­out the tri­al to char­ac­ter­ize host-micro­bio­me inter­ac­tions and iden­ti­fy poten­tial response biomarkers.

Acknowl­edge­ments: We thank Nadim Aja­mi and Jen­nifer War­go of the MD Ander­son Can­cer Cen­ter for their con­tin­ued sup­port. 

Down­load Poster