Immune-related enterocolitis in patients with cancer undergoing immunotherapy
Conditions
Interventions
Group 1: Fecal Microbiota Transplantation (FMT)
Sponsors
Universitätsspital Zürich
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Inclusion criteria
Inclusion criteria: General inclusion criteria for all participants: • Individuals must be at least 18 years of age and can be male or female • Able to understand and sign the informed consent, obtained from subject according to local regulations. Two groups of participants will be included based on the following criteria: 1. FMT-Donors: healthy individuals 2. FMT-Recipients: Patients with malignancies treated with immune-checkpoint inhibitors who developed grade II-IV immune-related enterocolitis either (i) refractory to steroids, ii) refractory to steroids and biologics (standard of care) or (iii) undergoing FMT as a first line therapy. Inclusion criteria FMT-Recipients: 1. Patients, at maximum of 75 years of age. 2. Confirmed diagnosis of grade II-IV immune-related enterocolitis with diarrhea and/or colitis related symptoms (e.g. bleeding, pain, mucus in the stool). 3. Absence of active systemic infections, coagulation disorders or other active major medical illnesses (per judgement of the investigator). 4. ECOG performance status of 0-1 5. Willingness to receive FMT administered via colonoscopy and undergo necessary bowel preparation pre-procedure. 6. Adequate organ function as determined by standard-of-care lab and according to the investigator’s discretion. 7. Following laboratory parameters need to be met: a. Platelet count = 50 x 109 / L b. Lymphocyte count = 0.8 x 109 / L c. Neutrophil count = 0.5 x 109 / L d. Hemoglobin = 8.5 g/dL e. Prothrombin time (PT)-international normalized ration (INR) = 1.5 f. ALT/AST < 3 × the upper limit of normal (ULN)serum g. Serum creatinine clearance (eGFR) = 50 mL/min h. total bilirubin = 20 µmol/L, except in patients with Gilbert’s Syndrome who must have a total bilirubin < 50 µmol/L i. LDH level of = 1 × ULN 8. BMI <35 kg/m2 9. Willingness to complete recipient-specific questionnaires. 10. Female subjects of childbearing potential must be willing to use highly effective method of birth control (for both genders) before the FMT procedure. 11. Female subject of childbearing potential should have a negative urine pregnancy test within minimum 8 hours prior to receiving the study intervention (FMT), performed on site. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Inclusion criteria FMT-Donors: 1. Voluntary individuals, at maximum of 60 years of age. 2. Willingness to donate blood and stool samples for research purposes. 3. Willingness to complete donor-specific questionnaires. 4. Willingness to complete donor-specific blood and stool testing to evaluate infectious agents. 5. Tested negatively for all infectious agents specified. 6. Willingness to provide multiple stool samples.
Exclusion criteria
Exclusion criteria: The presence of any of the following exclusion criteria will lead to the disqualification of the participant: Exclusion criteria FMT Recipients: 1. Presence of absolute contra-indications to colonoscopy and/or FMT administration: - Toxic megacolon - Anatomic contra-indications to colonoscopy - Colectomy 2. Patient is currently participating and receiving other study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of this study intervention. 3. Currently under any form of systemic antibiotics. 4. Severe cardiac or pulmonary comorbidities (per judgement of the investigator), e.g.: - diagnosed heart failure with NYHA (New York Heart Association) classification > 2 - severe cardia arrhythmias, e.g. AV-block grade 3 - Unstable angina pectoris 5. Uncontrolled/untreated epilepsia. 6. Obesity = Grade 2 (BMI of 35 kg/m2 or above). 7. Functional or anatomic stenosis in the lower gastrointestinal tract. 8. Severe sleep apnea syndrome (OSAS) (per judgement of the investigator). 9. Had a severe hypersensitivity reaction to propofol. 10. Severe anaphylactic reaction to any food (food allergies, e.g. soya, chicken egg white). 11. Has serious concomitant illnesses. The eligibility can be granted by the treating investigator on individual bases. 12. Active systemic infections, coagulation disorders or other active major medical illnesses (per judgement of the investigator). 13. Treatment with antibiotics 4 weeks prior to study enrollment or expectation to receive antibiotics during the course of this study. 14. Has history or active infection of HIV infection or AIDS-related illness. 15. Has active infection of HBV and HCV. Patients with a history of Hepatitis B/C infection who might have received anti-viral therapy and are disease free may be considered for enrollment after discussion with Principal Investigator. 16. Patient has received a live vaccine within 4 weeks prior to the first dose of treatment. Seasonal influenza vaccines or COVID-19 vaccines for injection are generally inactivated virus vaccines and are allowed. 17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 18. Females who are pregnant or breastfeeding. 19. Current or foreseeable neutropenia (< 500 neutrophils /ul) within the next 14 days, scheduled or recent (< 100 days) allogeneic stem cell transplant (SCT) or active graft-versus-host-disease (GVHD) requiring immunosuppressive treatment. Exclusion criteria FMT Donors: Infectious diseases: 1. Positive serology/blood test indicative for infection with for HIV 1+2, HAV, HBV, HCV, HEV, HTLV 1+2, EBV, CMV, Treponema pallidum, Strongyloides stercoralis, Toxoplasmosis 2. Positive stool test for microbiology: Salmonella spp., Shigella spp., Campylobacter ssp., Clostridioides difficile, Yersinia enterocolitica, E. coli ssp. (z.B. EPEC / EHEC / ETEC / EAEC / EIEC), Plesiomonas shigelloides, Vibrio spp., Helicobacter pylori, Listeria monocytogenes, Tropheryma whipplei, Vancomycin-resistant Enterococcus faecium, Glycopeptid-resistente Enterococci, Methicillin Resistant Staphyloccocus Aureus, ESBL, Carbapenemase producing Enterobacteriacae and non-fermenting bacteria. 3. Positive stool test for virology: Adenovirus, Enterovirus (excl. Rhinovirus), Sapovirus, Astrovirus, Rotavirus, Norovirus. 4. Positive stool test for parasitology: Bla
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess the feasibility of a one-time FMT to modulate the frequency of cytotoxic CD8+ T-cells in the intestinal mucosa of immune-related enterocolitis patients 12 weeks after FMT (FMT-Recipients) as assessed by enumeration using immunostaining. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1) Evaluation of intestinal bacterial composition will be performed by metagenomics analysis. (12 weeks post-FMT) 2) Evaluation of baseline intestinal bacterial composition will be performed by metagenomics analysis. (Baseline). 3) Evaluation of intestinal bacterial diversity will be performed by metagenomics analysis. (12 weeks post-FMT) 4) Evaluation of the frequency of CD8+ T- cells in the circulation will be performed by cell enumeration using single cell RNA sequencing and/or flow cytometry. (12 weeks post-FMT) 5) Quality and functionality of CD8+ T-cells in intestinal tissue from immune-related enterocolitis patients will be assessed by single cell RNA sequencing and/or flow cytometry. (12 weeks post-FMT) 6) Quality and functionality of CD8+ T-cells in circulation of immune-related enterocolitis patients will be assessed by single cell RNA sequencing and/or flow cytometry. (12 weeks post-FMT) 7) PBMC composition in immune-related enterocolitis patients will be assessed by single cell RNA sequencing and/or flow cytometry. (12 weeks post-FMT) 8) Composition of innate and adaptive immune cell subsets in the intestine of FMT recipients will be assessed by spatial transcriptomics and/or immunostaining-based approaches. (12 weeks post-FMT) 9) Composition of fecal and PBMC-derived microbiome will be assessed by metagenomics analysis. (12 weeks post-FMT) 10) Composition of the serum metabolome will be assessed by mass spectrometry. (12 weeks post-FMT) 11) Composition of the serum, intestinal tissue-derived and PBMC-derived proteome will be assessed by proteomics analysis. (12 weeks post-FMT) 12) Composition of the immune cells within intestinal tissue will be assessed by transcriptomics and/or immunostaining-based approaches. (12 weeks post-FMT) 13) Safety outcomes (12 weeks post-FMT) will be assessed based on: a. Incidence of adverse events (AEs) related to FMT b. Incidence of serious adverse events (SAEs) related to FMT 14) Quality of li | — |
Countries
Switzerland
Contacts
Public ContactMichael Scharl
Universitätsspital Zürich
Outcome results
None listed