Clinical trial NCT03171220: Neoantigen Reactive T Cells Combined With SHR-1210 for Chinese Patients With Advanced Refractory Solid Tumors
Official title: Single Center Single Arm Clinical Prospective Study of Neoantigen Reactive T Cells (NRTs) Combined With Programmed Cell Death-1（PD-1） Inhibitor in the Treatment of Chinese Patients With Advanced Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Advanced Malignant Solid Tumor
Keywords: Neoantigen
Neoantigen Reactive T cells (NRTs)
PD-1 Inhibitor
Advanced Solid Tumor
Adoptive Cell Therapy(ACT)
PD-1 antibody
SHR1210
Lead sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Sponsor class: OTHER
First posted: 2017-05-31
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with Adverse Events
timeFrame: up to 6 months
Secondary outcomes:
measure: Response Rate
timeFrame: At 3, 6 and 12 months
measure: Progression free survival (PFS)
timeFrame: At 6,9 and 12 months
Other outcomes:
measure: Overall Survival (OS)
timeFrame: At 6,12 and 18 months
measure: Interferon-gama change of PBMC cells in the peripheral blood stimulated by tumor antigens
timeFrame: At baseline,40days,2 months,6 months and at the time of disease progress
measure: Th1/Th2 change in the peripheral blood
timeFrame: At baseline,40days,2 months,6 months and at the time of disease progress
Locations:
city: Nanjing
country: China
facility: The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
state: Jiangsu
Study officials:
affiliation: The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital
name: Baorui Liu, M.D & Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, Trebska-McGowan K, Wunderlich JR, Yang JC, Rosenberg SA. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016 Apr;22(4):433-8. doi: 10.1038/nm.4051. Epub 2016 Feb 22.
citation: Desrichard A, Snyder A, Chan TA. Cancer Neoantigens and Applications for Immunotherapy. Clin Cancer Res. 2016 Feb 15;22(4):807-12. doi: 10.1158/1078-0432.CCR-14-3175. Epub 2015 Oct 29.
citation: Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967.
citation: Su S, Zou Z, Chen F, Ding N, Du J, Shao J, Li L, Fu Y, Hu B, Yang Y, Sha H, Meng F, Wei J, Huang X, Liu B. CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology. 2016 Nov 22;6(1):e1249558. doi: 10.1080/2162402X.2016.1249558. eCollection 2017.
citation: Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA, Hinrichs CS. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017 Apr 14;356(6334):200-205. doi: 10.1126/science.aak9510.
citation: Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255-2262. doi: 10.1056/NEJMoa1609279.
citation: Parkhurst M, Gros A, Pasetto A, Prickett T, Crystal JS, Robbins P, Rosenberg SA. Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression. Clin Cancer Res. 2017 May 15;23(10):2491-2505. doi: 10.1158/1078-0432.CCR-16-2680. Epub 2016 Nov 8.
citation: Chen F, Zou Z, Du J, Su S, Shao J, Meng F, Yang J, Xu Q, Ding N, Yang Y, Liu Q, Wang Q, Sun Z, Zhou S, Du S, Wei J, Liu B. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J Clin Invest. 2019 Mar 5;129(5):2056-2070. doi: 10.1172/JCI99538. Print 2019 May 1.