Back­ground: Immune check­point inhibitors (ICI) have trans­formed can­cer ther­a­py but are fre­quent­ly com­pli­cat­ed by immune-relat­ed adverse events (irAEs), par­tic­u­lar­ly immune-relat­ed diar­rhea or col­i­tis (irCol­i­tis), which can neces­si­tate immuno­sup­pres­sion and ICI dis­con­tin­u­a­tion. Fecal micro­bio­ta trans­plan­ta­tion (FMT) has shown promise in treat­ing irCol­i­tis, but con­cerns around donor vari­abil­i­ty, infec­tion risk, and scal­a­bil­i­ty lim­it the util­i­ty and scal­a­bil­i­ty of FMT. KAN-004 is a defined live bio­ther­a­peu­tic prod­uct (LBP) com­posed of >100 com­men­sal strains, ratio­nal­ly select­ed from FMT-qual­i­fied healthy human donors to restore gut micro­bial com­po­si­tion, meta­bol­ic func­tion, and micro­bio­me-immune bal­ance in patients with irColitis. 

Meth­ods: Pre­clin­i­cal stud­ies eval­u­at­ed the impact of KAN-004 in two murine mod­els of antibi­otics-induced dys­bio­sis, and an acute dex­tran sodi­um sul­fate (DSS)-induced col­i­tis mod­el. Fur­ther, the impact of KAN-004 as a co-treat­ment con­cur­rent with anti-PD‑1 ther­a­py was inves­ti­gat­ed in two tumor mod­els (MCA-205 in germ-free mice and E0771 in SPF mice). End­points includ­ed micro­bial engraft­ment, metabo­lite recov­ery, histopatho­log­ic scor­ing, clin­i­cal col­i­tis indices, tumor response and flow cytometry. 

Results: In murine mod­els oral sup­ple­men­ta­tion of KAN-004 achieved rapid, durable engraft­ment with strain detec­tion by day 2 and sus­tained lev­els through day 60. While tar­get­ed Short Chain Fat­ty Acids (SCFAs) were unde­tectable at base­line fol­low­ing antibi­ot­ic pre-treat­ment, KAN-004 restored a naïve-like SCFA pro­file by day 9, unlike the delayed and imbal­anced recov­ery seen with vehi­cle. In an DSS col­i­tis mod­el, KAN-004 sig­nif­i­cant­ly improved sur­vival (80% vs. 10%, p = 0.0027), reduced clin­i­cal sever­i­ty (p = 0.002), and pre­served epithe­lial bar­ri­er integri­ty. When com­bined with anti-PD‑1 ther­a­py in an MCA-205 tumor mod­el, KAN-004 enhanced anti-PD‑1 effi­ca­cy (p = 0.008) com­pared to…. In an E0771 ICI resis­tant tumor mod­el, com­bi­na­tion anti-PD1 and KAN-004 treat­ment showed a trend for decrease in tumor size com­pared to iso­type con­trol (p = 0.055), with increased tumor infil­tra­tion of CD8+ effec­tor T cells com­pared to FMT from ICI respon­der donors (p = 0.02). 

Con­clu­sions: KAN-004 demon­strates pre­clin­i­cal effi­ca­cy in resolv­ing irCol­i­tis and enhanc­ing anti­tu­mor immu­ni­ty in ICI-treat­ed mod­els. Nov­el method devel­op­ments by Kan­vas Bio­sciences pro­vide pre­cise strain-lev­el com­po­si­tion for assess­ing micro­bial kinet­ics and GMP man­u­fac­tur­ing. In col­lab­o­ra­tion with the Cen­tre Hos­pi­tal­ier de l’U­ni­ver­sité de Mon­tréal (CHUM), a phase I clin­i­cal tri­al of KAN-004 in patients with irCol­i­tis is planned to begin in Q4 2025. 

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