CD19 CAR-T Expressing IL7 and CCL19 Combined With PD1 mAb for Relapsed or Refractory Diffuse Large B Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for 35% of lymphoma. Chimeric antigen receptor T cell (CAR-T) therapy is a new method to treat DLBCL. KTE-C19, published in the New England Medical Journal in December 2017, was used to treat relapsed and refractory B-cell lymphoma. One year of treatment for 111 patients, the total response rate was 82%, and the complete remission rate was 54%. However, a large number of clinical studies have shown that about 20% of patients with B-ALL and 50% of patients with B-NHL cannot achieve complete remission (CR) after CD19-CAR-T treatment. Targeting tumor microenvironment is an important new method to overcome the drug resistance of CAR-T cells. In this study, IL-7 and CCL19 were connected on the basis of traditional second generation CD19 CAR-T cells to construct novel fourth generation CAR-T cells, which can promote the infiltration, accumulation and survival of CAR-T cells in lymphoma tissue, and further enhance the anti-tumor effect of traditional CAR-T cells. At the same time, combined with four generations of CAR-T cells and PD1 monoclonal antibody, PD1 / PDL1 signal pathway was blocked, anti-tumor effect of CAR-T was improved, and immune response and long-term remission rate of DLBCL were improved.


Eligibility Criteria:
Inclusion Criteria:

* (1) Age ≥ 18, upper limit 75, unlimited for men and women;

  (2) ECOG score 0-3;

  (3) Histologically confirmed diffuse large B-cell lymphoma (DLBCL) \[according to who 2008\];

  (4) CD19 was positive (immunohistochemistry or flow cytometry).

  (5) The definition of refractory or relapse of DLBCL is: no complete remission after 2-line treatment; disease progression in any treatment process, or disease stabilization time equal to or less than 6 months; or disease progression or relapse within 12 months after hematopoietic stem cell transplantation;

  (6) The previous treatment of diffuse large B cell lymphoma must include rituximab (CD20 mAb) and anthracycline;

  (7) There should be at least one measurable focus. It is required that any length of lymph node focus should be greater than 1.5cm or any length of extranodal focus should be greater than 1.0cm. PET-CT scan focuses should have uptake (SUV is greater than liver blood pool);

  (8) The absolute value of neutrophils in peripheral blood ≥ 1000 / μ L, platelet ≥ 45000 / μ L;

  (9) Heart, liver and kidney function: creatinine \< 1.5mg/dl; ALT (alanine aminotransferase) / AST (aspartate aminotransferase) 2.5 times lower than the normal upper limit; total bilirubin \< 1.5mg/dl; heart ejection fraction (EF) ≥ 50%;

  (10) Sufficient understanding ability and voluntary signing of informed consent;

  (11) Those with fertility must be willing to use contraceptive methods;

  (12) According to the judgment of the researchers, the expected survival time is more than 4 months;

  (13) Willing to follow visit schedule, administration plan, laboratory inspection and other test steps.

Exclusion Criteria:

* (1) History of other tumors;

  (2) Hematopoietic stem cell transplantation was performed within 6 weeks;

  (3) Any target car-t treatment was performed within 3 months before the car-t treatment;

  (4) Previous use of any commercially available PD-1 mAb;

  (5) Cytotoxic drugs, glucocorticoids and other targeted drugs were received within 2 weeks before cell collection;

  (6) Active autoimmune diseases;

  (7) Uncontrollable infection of active bacteria and fungi;

  (8) HIV infection, syphilis infection; active hepatitis B or C: hepatitis B: HBV-DNA ≥ 1000IU / ml; hepatitis C: HCV RNA positive and liver function abnormal.

  (9) Known central nervous system lymphoma.