Safety and Efficacy of CD207 Targeted CAR-T Cell Therapy in Patients With R/R Langerhans Cell Histiocytosis

Study Overview
=================
Brief Summary
-----------------
This is a single-arm study to evaluate the efficacy and safety of CD207 targeted CAR-T cell therapy in relapsed and refractory langerhans cell histiocytosis.

Detailed Description
-----------------
There are limited options for treatment of r/r langerhans cell histiocytosis. CD207 is expressed on the membrane surface of langerhans cells，and it is an ideal target for CAR-T. In this study, investigators will evaluate the safety and efficacy of CD207 targeted CAR- T cell therapy in patients with r/r langerhans cell histiocytosis. The primary goal is safety and efficiency assessment, including incidence and severity of adverse events and overall response rate.

Official Title
-----------------
Safety and Efficacy of CD207 Targeted CAR-T Cell Therapy in Patients With Relapsed and Refractory (R/R) Langerhans Cell Histiocytosis

Conditions
-----------------
Langerhans Cell Histiocytosis

Intervention / Treatment
-----------------
* Biological: CD207 CAR-T cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Relapsed or refractory langerhans cell histiocytosis, defined as: 1) any relapse during standard chemotherapy; 2) not responding to standard chemotherapy; 3) not achieving CR after first cycle of second-line chemotherapy for relapsed langerhans cell histiocytosis; 3-65 years old; Expected survival time ≥ 3 months; ECOG performance status of 0 or 1 (age ≥ 16 years) or Karnofsky performance status> 80 (age < 16 years) ; With single or venous blood collection standards, and no other cell collection contraindications; WBC ≥ 2.5×10^9/L ，LY ≥ 0.7×10^9/L，LY% ≥15%; Serum creatinine ≤ 2.0 mg/dl; ALT/AST ≤ 2.5 x ULN; Total bilirubin ≤ 2.0 mg/dl; PT:INR<1.7, or PT is within 4s of the normal value; Ability and willingness to adhere to the study visit schedule and all protocol requirements. Exclusion Criteria: Transduced CAR+ T lymphocytes<5%, or expansion <5 folds after stimulation with anti CD3/anti CD28 beads; Pregnant or breasting-feeding women; Active hepatitis B or hepatitis C infection; Patients with HIV infection; Uncontrolled active infection; Use of systemic corticosteroid therapy; Have received gene therapy, or any other CAR-T treatment; Allergic to immunotherapy and related drugs; History of heart disease requiring treatment, or poorly controlled hypertension; Preceding and/or ongoing active ulcer or gastrointestinal bleeding; Have received allogeneic hematopoietic stem cell transplantation, or eligible for allogeneic hematopoietic stem cell transplantation; Severe central nervous system involvement; Severe lung involvement; Hyponatremia (serum sodium<125mmol/L); Hypokalemia (Serum kalium<3.5mmol/L); Those who need long-term anticoagulation treatment (warfarin or heparin); Those who need long-term antiplatelet treatment (aspirin, dose>300mg/d; clopidogrel, dose>75mg/d); Radiation therapy within 4 weeks prior to registration; Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina, cardiac arrhythmias, mental illness, and other diseases that in the opinion of the investigator would pose an unacceptable risk to the subject; Have a history of severe allergy; Current enrollment in another study; Patients with other contraindications considered unsuitable for participation in this study (according to investigator's judgement).

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 65 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: CD207 CAR-T cells<br>Cohort 1 will receive 1 x 10^6 CAR+ T cells/kg. Cohort 2 will receive 3 x 10^6 CAR+ T cells/kg. Cohort 3 will receive 5 x 10^6 CAR+ T cells/kg. Cohort 4 will receive 1 x 10^7 CAR+ T cells/kg. | Biological: CD207 CAR-T cells<br>* Single dose of CD207 CAR-T cells administered IV<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The number of cases with complete response (CR) and partial response (PR) after treatment as a percentage of the total cases. | 2 years | 
| Incidence and Severity of Adverse Events (AEs) | Treatment-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) of CD207 CAR-T cell therapy in patients with r/r langerhans cell histiocytosis | PFS will be assessed from the first CAR-T cell infusion to death from any cause or the first assessment of progression. | 2 years | 
| Overall Survival (OS) of CD207 CAR-T cell therapy in patients with r/r langerhans cell histiocytosis | OS will be assessed from the first CAR-T cell infusion to death from any cause. | 2 years | 
| Effects of CD207 CAR-T cells on human immune system | Dynamic changes of T cell subset and immune globulin. | 2 years | 
| Metabolism of CAR T-cells in vivo | Absorption, distribution and metabolism of CD207-CAR T cells in vivo. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CAR-T cell therapy, Langerhans Cell histiocytosis, CD207