CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Be willing and able to provide written informed consent.
* Histologically confirmed pMMR or MSS mCRC
* Male or female, aged ≥ 18 years
* Life expectancy greater than 12 weeks
* ECOG performance status \<2
* Patient suitable for the collection of biological material from leukapheresis: negative serological tests (HIV, HBV, HCV, Treponema pallidum); normal cardiological parameters (12-lead ECG and echocardiogram); evaluation by transfusionist to exclude possible contraindications to leukapheresis; recovered (grade 1 or less by CTCAE 5.0) from all the adverse events related to previous treatments.Exclusion Criteria:
* Patients must have measurable disease by RECIST v 1.1 criteria on CT (or MRI) scan of the chest, abdomen and pelvis. See section 9.2 and Appendix D for the evaluation of measurable disease.
* Prior treatment with 1-2 chemotherapy regimens in an advanced setting, including (if not contraindicated) fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody and/or anti-EGFR monoclonal antibody for RAS wild-type tumors.
* Patients must have normal organ and marrow function as defined below:

leukocytes \>3,000/μL, absolute neutrophil count \>1,500/μL, platelets \>100,000/μL, total bilirubin \< 1.5 X institutional upper limit of normal (ULN), AST(SGOT)/ALT(SGPT) \<2.5 X ULN, creatinine \< 1.5 X ULN OR creatinine clearance \>30 mL/min/1.73 m2

* The autologous surgical specimen needed for vaccine manufacturing must have been collected and sent to the Somatic Cell Therapy Lab of IRCCS IRST and must fulfill all the acceptance criteria prescribed by the GMP procedures
* Recovery (grade 1 or less by CTCAE 5.0) from all the adverse events related to previous surgery.
* A female participant is eligible to participate if she is not pregnant and not breastfeeding. Female patients of childbearing potential and all male patients must accept and be compliant with a highly effective contraceptive method
* Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

* Prior treatment with FTD/TPI for mCRC
* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
* Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
* Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab, FTD/TPI, Bevacizumab or components of the DC vaccine.
* History of congenital or acquired immunodeficiency, including history of organ transplantation.
* Any active inflammatory or autoimmune disease requiring systemic steroids or other immunomodulatory agents
* Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix).

主要终点：Overall Response Rate (ORR) · The primary endpoint is Overall Response Rate (ORR) of chemotherapy, defined as the percentage of patients experiencing partial response (PR) or complete response (CR), according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, after starting the treatment with FTD/TPI plus Bevacizumab. · 2 years
次要终点：Progression free survival (PFS)；Safety evaluation；Overall Survival (OS)；In vivo immunomonitoring through DTH test:；Characterization of patient's HLA class I immune response；Characterization of patient's HLA class II immune response；Characterization of patient's HLA-restricted immune response；Definition of the prognostic and predictive role of peripheral immune cell subsets and soluble factors

• Sequential immunochemotherapy with Pembrolizumab plus DC Vaccine, followed by FTD/TPI + Bevacizumab · EXPERIMENTAL · Induction phase: In the immunological induction phase patients will be given DCs intradermally every week for up to 4 doses and then a further administration after 3 weeks and Pembrolizumab 200 mg IV q3w for up to 3 cycle. Maintenance phase: patients will receive FTD/TPI combined with Bevacizumab.Treatment with FTD/TPI and Bevacizumab will start regardless of the response obtained with the induction combo immunotherapy, and will continue until confirmed disease progression, unacceptable toxicity or withdrawal of the consent by the patient, whichever occurs first.

Single-arm, open-label, multicenter phase 2 clinical trial evaluating the clinical and the immunological activity of an innovative strategy with an induction combo immunotherapy (Pembrolizumab plus DC Vaccine) followed by a maintenance chemotherapy (FTD/TPI plus Bevacizumab) in patients with refractory MSS/pMMR metastatic colorectal cancer.