CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. ECOG performance status ≤2 and Estimated life expectancy of more than 3 months.
3. Local advanced/metastatic solid tumors confirmed by histopathology or cytology with documentation of tumor EphA2 positive (≥20%) and KRAS mutation (G12V or G12D or G12C) within 6 months prior to screening. The second malignancy is allowed.
4. No clinical response to standard frontline therapy, or no standard therapy exists. Patients who have declined standard therapy or have no access to standard therapy may be enrolled and the reasons for lack of access need to be documented. Previous treatment with anti-PD-1/PD-L1 antibodies or anti-CTLA4 antibody are allowed, regardless of the level of PD-1/PD-L1 expression, dMMR and TMB.
5. At least one measurable lesion at baseline per RECIST version 1.1.
6. Adequate organ function as defined by the following criteria: ANC ≥1000 cells/μL; Platelet count ≥80,000/μL; Hemoglobin ≥8.0 g/dL; Serum AST and serum ALT, ≤3.0 x ULN (≤5 x ULN for patients with liver metastases); Total serum bilirubin ≤3.0 x ULN); Serum creatinine ≤2 x ULN or creatinine clearance of ≥45 mL/min.
7. Willing to undergo either excised or large-needle lymph node or tissue biopsy, or provide formalin-fixed paraffin-embedded (FFPE) tumor tissue block or freshly cut unstained slides.
8. Willing to complete all scheduled visits and assessments at the institution administering therapy.
9. Able to read, understand and provide written informed consent.

Exclusion Criteria:

1. Having KRAS (G12V or G12D or G12C) germline mutation.
2. Active central nervous system disease involvement (but allow patients with prior brain metastases treated at least 4 weeks prior to enrollment that are clinically stable and do not require intervention), or prior history of NCI CTCAE Grade ≥3 drug-related CNS toxicity.
3. Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation.
4. Evidence of active uncontrolled viral, bacterial, or systemic fungal infection.
5. Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
6. Active infection of hepatitis B virus (HBV), or hepatitis C virus (HCV).
7. Patients with history (within the last 5 years) or risk of autoimmune disease who have immunosuppressive medications or immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone or equivalent) within 28 days prior to enrollment. However, patients who received a short course of corticosteroids (eg, premedication prior to antibody drug) will be eligible for study entry.
8. Major trauma or major surgery within 4 weeks prior to enrollment.
9. Previous treatment involving KRAS mutant (G12V or G12D or G12C) and EphA2.
10. Systemic chemotherapy and other intervene within 2 weeks prior to vaccination.
11. Being participating or withdrew any other trials within 4 weeks.
12. Any serious underlying medical (eg, pulmonary, renal, hepatic, gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements.
13. Vaccination within 30 days of study enrollment.
14. Pregnant, lactating, or breastfeeding females.
15. Researchers believe that other reasons are not suitable for clinical trials.

主要终点：Incidence of treatment related adverse events (AEs) · Determining the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0. AEs such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. · 2 years；Clinical Response · Clinical response will be determined by RECIST 1.1 and iRECIST criteria. Response rate is the proportion of patients that achieve CR and PR. · 2 years；Disease Control · Disease control will be determined by RECIST 1.1 and iRECIST criteria. Disease control rate is the proportion of patients that achieve CR, PR and SD. · 2 years；Immune Response · Immune response will be evaluated by phenotype and functional analysis of vaccine-reactive T cells and Neoantigen-reactive T cells as well as other immune cells in peripheral blood and tumor samples. Response is defined by ≥3 folds increase relative to pre-vaccination. · Peripheral blood: baseline, weekly before Week 9, prior to each vaccination after Week 9 until last vaccination and 1 year after last vaccine. Tumor tissue: baseline, Week 3, and following timing will be performed according to subject's condition.
次要终点：Progression Free Survival (PFS)；Overall Survival (OS)；Time to response (TTR)；Duration of response (DOR)；Number and copy number of KRAS-EphA-2-CAR-DCs；The level of cytokines in serum

• KRAS-EphA-2-CAR-DC · EXPERIMENTAL · In the priming phase, a conditioning chemotherapy regimen of Abraxane and cyclophosphamide is administered three days before vaccination, and KRAS-EphA-2-CAR-DC vaccine is infused on Day 0 and Day 7 in Week 1. In the boost phase, KRAS-EphA-2-CAR-DC vaccine is infused one dose every 4 weeks since Week 5 for a total of 6 to 8 doses, then maintenance vaccination is given one dose every 8 weeks, until: 1. Unacceptable toxicity occurred or disease progression; or 2. Reactive T cells are undetected repeatedly after the last vaccine dose; or 3. Vaccine exhaustion.
• KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody · EXPERIMENTAL · In the priming phase, a conditioning chemotherapy regimen of Abraxane and cyclophosphamide is administered three days before vaccination, and KRAS-EphA-2-CAR-DC vaccine is infused on Day 0 and Day 7 in Week 1. In the boost phase, KRAS-EphA-2-CAR-DC vaccine is infused one dose every 4 weeks since Week 5 for a total of 6 to 8 doses, then maintenance vaccination is given one dose every 8 weeks. Anti-PD-1 antibody is administered 2 days after the first dose of KRAS-EphA-2-CAR-DC vaccine in the boost phase (Day 3 in Week 5) and every 4 weeks afterwards, until: 1. Unacceptable toxicity occurred or disease progression; or 2. Reactive T cells are undetected repeatedly after the last vaccine dose; or 3. Vaccine exhaustion.
• KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody · EXPERIMENTAL · In the priming phase, a conditioning chemotherapy regimen of Abraxane and cyclophosphamide is administered three days before vaccination, and KRAS-EphA-2-CAR-DC vaccine is infused on Day 0 and Day 7 in Week 1. In the boost phase, KRAS-EphA-2-CAR-DC vaccine is infused one dose every 8 weeks since Week 5. Anti-PD-1 antibody and anti-CTLA4 antibody are administered 2 days after the first dose of KRAS-EphA-2-CAR-DC vaccine in the boost phase (Day 3 in Week 5) and every 3 weeks afterwards for four doses, followed by anti-PD-1 antibody once every 3 weeks, until: 1. Unacceptable toxicity occurred or disease progression; or 2. Reactive T cells are undetected repeatedly after the last vaccine dose; or 3. Vaccine exhaustion.

This is a pilot clinical trial for subjects with local advanced/metastatic solid tumors to determine the safety, efficacy and immune response of autologous EphA2-targeting CAR-DC vaccine loaded with KRAS mutant peptide (KRAS-EphA-2-CAR-DC) in combination with ICIs. It aims to: assess the safety and antitumor effects of KRAS-EphA-2-CAR-DC vaccine; detect T cell response against KRAS mutant peptide and tumor neoepitopes after the treatment with KRAS-EphA-2-CAR-DC vaccine and ICIs.