Neoantigen Reactive T Cells Combined With SHR-1210 for Chinese Patients With Advanced Refractory Solid Tumors (NRT-01)

Nanjing University

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Advanced Malignant Solid Tumor

Treatments: Drug: Cyclophosphamide; Biological: SHR-1210; Biological: Interleukin-2; Drug: Fludarabine; Biological: Neoantigen Reactive T Cells(NRTs)

Study type: Interventional

Funder types: Other

Identifiers

NCT03171220

NDTHNanjing

Details and patient eligibility

About

The purpose of this study is to see the safety and efficient of neoantigen reactive T cells (NRTs) combined with programmed cell death-1(PD-1) inhibitor（SHR-1210）in the treatment of Chinese patients with advanced refractory solid tumors.

Full description

The tumor-specific "none-self" immunogenic neoantigens encoded by either viral genes or somatic mutation genes, possess the potential to induce specific anti-cancer immunity, including cellular and humoral immune responses. Today, numerous clinical trials demonstrate that although these "none-self" antigens initiate the antigen-specific immunoglobulin G antibodies and cluster of differentiation 4（CD4）+/cluster of differentiation 8（CD8）+T-cells response, not all of them show a clinical benefit in the response rate, progression-free survival or overall survival.Immune tolerance induced by PD-1 or programmed cell death-ligand1（ PD-L1）maybe play a vital role for these negative outcomes.Personalized cell therapy plus checkpoint inhibitors maybe own a breakthrough in the treatment of those malignant diseases without standard options.Our center has successfully established a new method for preparing personalized neoantigen reactive T cells(NRTS) for adoptive cell therapy(ACT). Today, we will carry out a single center single arm clinical prospective study of NRTs combined with PD-1 inhibitor(SHR-1210) for the treatment of Chinese patients with advanced refractory solid tumors. Participants are assigned to receive 4 circles of cell therapy,and prior to each cycle's immunocytes treatment,preconditional chemotherapy and SHR-1210 will be carried out, and IL-2 continuous intravenous infusion（CIV） will also be given for 5 consecutive days after each time's cell infusion. The safety and clinical response rate（RR） are evaluated. Biomarkers and immunological markers are also monitored.

Enrollment: 40 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adult patients aged 18 to 75 years old
• Histologic or cytologic confirmation of advanced refractory solid tumors with no available curative treatment options
• At least one measurable disease: diameter ≥20mm or spiral computed tomography(CT)≥10mm; and can providing with tumor specimen (for testing the expression of PD -L1 and the infiltrating lymphocytes)
• Must be human leukocyte antigen (HLA)-A2/A24/A11 positive
• Eastern Cooperative Oncology Group(ECOG)<0-2 and expected survival time 3 months or more
• At least one new antigen can induce T cell secrete interferon - gamma (IFN - gamma) twice as normal controls during the new antigens screening
• Without anticancer treatment more than one month
• Hematology Index including: Neutrophile granulocyte greater than 1.5×10^9/L; Hemoglobin greater than 10g/dL; Platelet greater than 100×10^9/L
• Biochemical index including: Serum bilirubin not greater than 1.5x upper limit of reference range (ULN); glutamic-pyruvic transaminase（ALT） or glutamic-oxalacetic transaminase（AST） not greater than 2.5x ULN; Creatinine clearance no less than 60ml/min
• Peripheral venous channel open and no contraindications to separating lymphocytes
• Negative pregnancy test for women of childbearing potential, and patients must be willing to practice birth control during the regimen
• Provision of informed consent
• Be able to follow the research program and follow up process

Exclusion criteria

• Those who now are undergoing other antitumor drug therapy (including chemotherapy, systemic steroids therapy, surgery, target therapy or immune therapy);
• Prior treatment with PD-1 monoclonal antibody(mAb） or PD-L1 mAb;
• Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix;
• History with pulmonary tuberculosis, and positive tests for Acquired Immune Deficiency Syndrome(HIV),hepatitis C virus(HCV),hepatitis B virus(HBV);
• Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism; Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure > class II New York Heart Association(NYHA), heart block >II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm).
• Evidence with central nervous system(CNS) disease
• Pregnant or nursing
• Psychiatric medicines abuse without withdrawal, or history of psychiatric illness.
• Hypersensitivity to investigational drugs or its components.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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40 participants in 1 patient group

Neoantigen Reactive T Cells + SHR-1210

Experimental group

Description:

Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5\~1 x 10\^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.

Treatment:

Drug: Fludarabine

Biological: Interleukin-2

Drug: Cyclophosphamide

Biological: Neoantigen Reactive T Cells(NRTs)

Biological: SHR-1210