A Study of Combination of Anti-PD1 Antibody-activated TILs and Chemotherapy in Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
This study was a phase I/II trial initiated by the investigator to evaluate the safety and tolerability of anti-programmed cell death protein 1 (anti-PD1) antibody-activated autologous tumor-infiltrating lymphocytes (TILs) combined with adjuvant chemotherapy in participants with stage III colon cancer. Twenty participants were enrolled and anti-PD1 antibody-activated TILs was infused into participants after the final of adjuvant chemotherapy to assess the safety and 3-year disease-free survival.

Detailed Description
-----------------
Postoperative colon cancer participants received 4 to 8 cycles of XELOX regimen adjuvant chemotherapy and received anti-PD1 antibody-activated TILs on the day 15 of the final cycle of chemotherapy. Fresh tumor tissues or sentinel lymph nodes were collected from participants with postoperative colon cancer, and the tumor tissues were digested with type IV collagenase at 37 °C for 2 to 4 hours. The cell pellet was washed, suspended in medium containing 10% AB serum, planted in a 24-well cell culture plate, and periodically changed according to the growth of the cells. After culturing for 2 to 3 weeks, TILs were co-stimulated with radioactively irradiated allogeneic peripheral blood mononuclear cells (PBMCs) and were expanded in 100 ml of Interleukin-2 (IL-2) medium in a cell culture flask. After rapid expansion for 15 days, the number of cells reached 0.1-1*10^10 cells. Before cell transfer, TILs were incubated with anti-PD-1 antibody, and a fraction of the TILs were collected to assess their number, phenotype, and viability of cells, and to test for possible contamination by bacteria, fungi, or endotoxins. Then, autologous TILs (0.1-1*10^10 cells) were transferred to participants via intravenous infusion.

Official Title
-----------------
A Phase I/II Study of Combination of Anti-Programmed Cell Death Protein 1(Anti-PD1) Antibody-activated Autologous Tumor Infiltrating Lymphocytes (TILs) and Chemotherapy in the Treatment of Stage III Colorectal Cancer.

Conditions
-----------------
Colorectal Cancer Stage III

Intervention / Treatment
-----------------
* Biological: anti-PD-1 antibody-activated TILs


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants with stage III colorectal cancer and scheduled to receive adjuvant chemotherapy postoperation. Age 18 to 75 years. Willing to sign a durable power of attorney. Able to understand and sign the Informed Consent Document. Life expectancy of greater than six months. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the preparative regimen. Adequate organ function. Serology: Seronegative for HIV antibody. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus. •Hematology: white blood cell count (> 3500/mm(3)). Platelet count greater than 100,000/mm(3). Hemoglobin greater than 9.0 g/dl. •Chemistry: Serum Alanine aminotransferase/Aspartate aminotransferase less or equal to 2.5 times the upper limit of normal. Serum creatinine less than or equal to 1.6 mg/dl. Total bilirubin less than or equal to 1.5 mg/dl. Exclusion Criteria: Previous treatment with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) , anti-PD-1, and anti-Programmed death-ligand 1(PD-L1). Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. Allogeneic tissue/organ transplantation. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). History of autoimmune disease Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). Concurrent antineoplastic therapies and systemic steroid therapy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD1-TIL combined with chemotherapy<br>Participants would received anti-PD-1 antibody-activated TILs after the final adjuvant chemotherapy. | Biological: anti-PD-1 antibody-activated TILs<br>* Participants would received one dose anti-PD-1 antibody-activated TILs at the final cycle of XELOX regimen chemotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS） | DFS is defined as the time from surgery until tumor recurrence or death. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is defined as the time from surgery until death from any cause | 6 months | 
| Severity of adverse events | According to National Cancer Institute Common Terminology Criteria for Adverse Events（NCI-CTCAE) | 3 weeks | 
| Immune cell subgroup and cytokine level | The number and secreted cytokines of cluster of differentiation 3 (CD3+), CD8+, CD4+ or CD56+ T cells | 1 months | 
| The quality of life by EQ-5D-5L (EuroQol Group, Chinese versions ) | Participants were interviewed with the EQ-5D-5L (EuroQol Group, Chinese versions). There are numbers from 0 to 100 on this scale of the EQ-5D-5L. 100 represents the best health condition you can imagine, and 0 represents the worst health condition in your imagination. Please put an X on the scale to indicate how healthy you are today. And the number you marked on the scale represents your health condition today. | 3 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Colorectal Cancer, TIL, immunotherapy