Clinical Study of IM96 CAR-T Cell Therapy in Patients With Advanced Colorectal Cancer

Inclusion Criteria:

1. The age is 18 to 75 years (including boundary values) and the gender is not limited;

2. Patients with advanced GI tumors diagnosed by pathohistology, mainly:

(1)Patients with metastatic colorectal cancer who have failed or are intolerant to second-line and above standard therapy;

Notes:

1. The standardized systemic treatment received by the patient must be in accordancewith the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Treatment ofColorectal and Gastric Cancer, 2024 Edition;

2. Claims of treatment intolerance: Patients who are unable to continue currenteffective systemic standardized treatment due to toxic side effects such as grade ≥3vomiting, diarrhea, abdominal pain, bone marrow suppression, etc., and who do notaccept refusal for financial and personal reasons; 3.Presence of at least onemeasurable lesion that meets RECIST 1.1 criteria; 4.Patients must provide a tumorsample within 2 years that meets the requirements (paraffin block or number ofunstained sections that meet the testing requirements set by the Institute) that ispositive for GUCY2C expression by immunohistochemistry; 5.Survival is expected to bemore than 3 months; 6.Eastern cooperative oncology group (ECOG) score of 0-1 (referto Attachment 2); 7.Women of childbearing potential who have a negative bloodpregnancy test prior to the start of the trial and who agree to use effectivecontraception during the trial and up to the last follow-up visit; male patientswhose partners are of childbearing potential agree to use effective contraceptionduring the trial and up to the last follow-up visit 8.Laboratory tests should meetat least the indicators specified below:

3. Hemoglobin (Hb) ≥ 90 g/L;

4. Neutrophil count (Absolute neutrophil count, ANC) ≥ 1.5 x 10^9/L;

5. Platelet count (PLT) ≥ 75 x 10^9/L;

6. Absolute lymphocyte value ≥ 0.6 x 10^9/L;

7. Lymphocytes make up ≥10% of white blood cells;

8. Creatinine clearance ≥60 ml/min;

9. Alanine transaminase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 x ULN andtotal bilirubin (TBL) ≤ 1.5 x ULN (for elevations of ALT and AST that can beexplained by hepatic aggression, the high limits for AST and ALT can beadjusted upward to 5-fold, and the high limit for TBL may be adjusted upward to 3-fold;

10. Serum albumin ≥ 3.0 g/dL.

11. Prolongation of prothrombinogen time ≤ 4s; 9.Left ventricular ejection fraction ≥ 50% with a normal ECG or an abnormal ECG that, in the judgment of theinvestigator, does not require treatment; 10.Oxygen saturation >92% innon-oxygenated state; 11.Vascular access is adequate for cell collection, andlines are available for patients with existing central venous catheters; Thosewho voluntarily participate in the trial and sign the informed consent form

Exclusion Criteria:

1. Presence of brain metastases;

2. Patients who have previously received or are awaiting an organ transplant;

3. Toxicity due to prior therapy not stabilized or recovered to ≤ grade 1 (except incases judged by the investigator to be not clinically significant);

4. Plasmapheresis (e.g., pleural effusion, abdominal effusion, pericardial effusion)with symptoms of compression that cannot be controlled with treatment;

5. Autoimmune disease requiring systemic immunosuppressive therapy (e.g., Crohn'sdisease, rheumatoid arthritis, systemic lupus) within 2 years prior to the start ofscreening;

6. Presence of chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and clinically significant pulmonary function test abnormalities;

7. Use of any of the following medications or treatments during the designated timeperiod prior to cell collection:

8. Therapeutic doses of corticosteroids have been used within 7 days prior to cellcollection. However, topical and inhaled steroids are permitted;

9. Received chemotherapeutic agents within 1 week prior to cell collection.Enrollment was allowed if the oral chemotherapeutic drug had passed at least 3half-lives prior to cell collection;

10. Those who used drugs to stimulate bone marrow hematopoietic cell productionwithin 5 days prior to cell collection;

11. Use of study drug within 4 weeks prior to cell collection. However, enrollmentwas allowed if the trial treatment was ineffective or the disease progressedduring the trial and at least 5 half-lives had elapsed prior to cellcollection;

12. Received interventional therapy, radiotherapy, ablation, and other localizedtreatments for the study disease within 4 weeks prior to cell collection;

13. Patients who have had major surgery or significant trauma within 4 weeks priorto cell collection or who are expected to require major surgery during thestudy period;

14. Received treatment with targeted agents such as regorafenib, furaquintinib,etc. within 1 week prior to cell collection;

15. Prior treatment with anti-GUCY2C target (unless GUCY2C target test remainspositive);

16. Those who have received other cell therapy or genetically modified cell therapy inthe past, such as TCR-T therapy, CAR-T therapy, etc;

17. If immunotherapy such as anti-PD1 and PD-L1 has been used prior to IM96 CAR-T celltransfusion, at least 5 half-lives must have elapsed after the last dose and beforeIM96 CAR-T cell transfusion;

18. Prior or clinically significant CNS disorders at screening, such as epilepsy,epileptic seizures, cerebrovascular disease (ischemia/hemorrhage/cerebralinfarction), cerebral edema, reversible posterior leukoencephalopathy, paralysis,aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellardisorders, organic brain syndromes, or psychiatric disorders;

19. Chronic or active infection requiring systemic therapy and history of symptomaticviral infection that has not been completely cured. For example, Hepatitis B:patients who are positive for Hepatitis B surface antigen (HBsAg) and/or Hepatitis Bcore antibody (HBcAb) and whose peripheral blood HBV-DNA test is above the lowerlimit of detection; patients who are positive for Hepatitis C Virus Antibody (HCVAb)and whose peripheral blood HCV-RNA test is above the lower limit of detection; andpatients infected with Human Immunodeficiency Virus (HIV), Syphilis;

20. Active EBV and cytomegalovirus, defined as patients with IgM antibody-positive orIgM antibody-negative but higher-than-normal EBV-DNA in EBV serum; andcytomegalovirus (CMV) seropositive or IgM antibody-negative but higher-than-normalCMV-DNA in serum;

21. Vaccination with live vaccine within 6 weeks prior to the start of screening;

22. Abnormalities of cardiac function include: long QTc syndrome or QTc interval >480ms; complete left bundle branch block, degree II/III AV block; severe, uncontrolledarrhythmias requiring pharmacologic therapy; history of chronic congestive heartfailure with NYHA class ≥3 (refer to Attachment 3) with a cardiac ejection fractionof less than 50% in the 6 months prior to screening; CTC AE ≥3 grade heart valvedisease; myocardial infarction, cardiac angioplasty or stenting, unstable angina,history of severe pericardial disease, or other clinically significant cardiacdisease within 6 months prior to screening;

23. Patients requiring anticoagulation therapy;

24. Requires long-term use of medications that can affect clotting (e.g., aspirin,warfarin, etc.);

25. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 monthsprior to initiation of screening;

26. Other untreated malignant tumors within the previous 5 years or concurrently, exceptcervical cancer in situ, basal cell carcinoma of the skin, and ductal carcinoma insitu of the breast;

27. Infections (fungal, bacterial, viral, or other) that require intravenousantimicrobial control or are uncontrollable, for simple urinary tract infections,and for bacterial pharyngitis, may be enrolled if the investigator evaluates thatthey can be controlled by curative treatment;

28. Patients with digestive tract obstruction;

29. Patients at high risk for bleeding or perforation;

30. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study; The presence of any factors affectingcompliance with the protocol or the patient's unwillingness or inability to complywith the procedures required in the study protocol, as determined by theinvestigator