Combination of CAR-DC Vaccine and PD-1 Antibody in Malignant Tumors

Sponsor

Chinese PLA General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT05631886

Collaborator

Zhejiang University (Other)

Enrollment

Location

Arm

47.9

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a pilot clinical trial for subjects with local advanced/metastatic solid tumors or relapsed/refractory (R/R) lymphomas to determine the safety, efficacy and immune response of autologous EphA2-targeting CAR-DC vaccine loaded with TP53 mutant peptide (TP53-EphA-2-CAR-DC) in combination with PD-1 antibody. It aims to: assess the safety and antitumor effects of TP53-EphA-2-CAR-DC vaccine; detect T cell response against TP53 mutant peptide and tumor neoepitopes after the treatment with TP53-EphA-2-CAR-DC vaccine and PD-1 antibody.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor, Adult Lymphoma EphA2 Overexpression TP53 R273H TP53 R175H TP53 R248Q TP53 R249S	Biological: TP53-EphA-2-CAR-DC Drug: Abraxane Drug: Cyclophosphamide Drug: PD-1 antibody	Phase 1

Detailed Description

Therapeutic cancer vaccines, especially DC-based vaccines, are extensively pursued immune approaches in addition to immune checkpoint blockade antibodies and chimeric antigen receptor T cells. DCs can engulf, process and present tumor antigens to T cells, thereby initiating a potent and tumor-specific immune response. However, clinical outcomes of therapeutic cancer vaccines still remain poor, with objective response rates that rarely exceed ~15%. The maturation and activation of DCs are necessary steps to trigger the antitumor responses. However, it is increasingly clear that tumor-infiltrating dendritic cells (TIDCs) usually have an immature or tolerated phenotype that plays central roles in developing tumor microenvironment (TME). As a consequence, malfunction of TIDCs could suppress the infiltration and function of tumor infiltrating T cells and convert them into immune suppressive regulatory T cells.

In our previous research, we constructed novel CAR-DCs (Chimeric antigen receptor engineered dendritic cells) containing a scFv domain targeting EphA2 antigen, CD8a transmembrane, tandem DC-specific activation domains. The engineered CAR-DCs were activated when contacting with tumor targets in TME, and consequently, augmented the cytotoxicity of antigen specific T cells in immune system humanized solid tumor mouse models. Our design of CAR-DCs provides an effective vaccine strategy for malignant tumors. Therefore, we designed an autologous CAR-DC vaccine engineered with anti-EphA2 CAR and TP53 mutant peptide (TP53-EphA-2-CAR-DC), which can suppress the growth of tumors expressing the correlated TP53 mutant in animal models. In addition, the combination of ICB inhibitors could further reverse immunosuppressive TME and globally activate T cell responses. In this pilot study, we aim to assess the safety, efficacy and immune response of TP53-EphA-2-CAR-DC combined with PD-1 antibody in patients with local advanced/metastatic solid tumors or R/R lymphomas.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pilot Clinical Trial of Autologous EphA-2-Targeting Chimeric Antigen Receptor Dendritic Cell Vaccine Loaded With TP53 Mutant Peptide Plus PD-1 Antibody for Local Advanced/Metastatic Solid Tumors or Relapsed/Refractory Lymphomas.

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Dec 30, 2025

Anticipated Study Completion Date :

Dec 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TP53-EphA-2-CAR-DC plus PD-1 antibody A conditioning chemotherapy regimen of Abraxane and cyclophosphamide is administered three days followed by TP53-EphA-2-CAR-DC vaccine which is administered on Day 0 and Day 7, as well as repeat every two weeks since Week 3, and PD-1 antibody is administered one day before each vaccine dose every two weeks since Week 3, until: Unacceptable toxicity occurred or disease progression; or Reactive T cells are undetected repeatedly after the last vaccine dose；or Vaccine exhaustion.	Biological: TP53-EphA-2-CAR-DC 5~10 × 10^6 DCs per dose will be administered by intravenous injection. Drug: Abraxane Intravenous abraxane 100~200 mg/m^2/day on day-5. Other Names: Abraxane Injectable Product Drug: Cyclophosphamide Intravenous cyclophosphamide 200~300 mg/m^2/day on day -4. Other Names: Cyclophosphamide for Injection Drug: PD-1 antibody Intravenous PD-1 antibody 200 mg/day. Other Names: PD-1 blocking antibody

Arm

Intervention/Treatment

Experimental: TP53-EphA-2-CAR-DC plus PD-1 antibody

A conditioning chemotherapy regimen of Abraxane and cyclophosphamide is administered three days followed by TP53-EphA-2-CAR-DC vaccine which is administered on Day 0 and Day 7, as well as repeat every two weeks since Week 3, and PD-1 antibody is administered one day before each vaccine dose every two weeks since Week 3, until: Unacceptable toxicity occurred or disease progression; or Reactive T cells are undetected repeatedly after the last vaccine dose；or Vaccine exhaustion.

Biological: TP53-EphA-2-CAR-DC

5~10 × 10^6 DCs per dose will be administered by intravenous injection.

Drug: Abraxane

Intravenous abraxane 100~200 mg/m^2/day on day-5.

Other Names:

Abraxane Injectable Product

Drug: Cyclophosphamide

Intravenous cyclophosphamide 200~300 mg/m^2/day on day -4.

Other Names:

Cyclophosphamide for Injection

Drug: PD-1 antibody

Intravenous PD-1 antibody 200 mg/day.

Other Names:

PD-1 blocking antibody

Outcome Measures

Primary Outcome Measures

Incidence of treatment related adverse events (AEs) [2 years]
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.
Clinical Response [2 years]
Clinical Response will be determined by iRECIST criteria. Response rate is the proportion of patients that achieve CR or PR.
Immune Response [Peripheral blood: baseline, weekly before Week 9, prior to each vaccination after Week 9 until last vaccine and 1 year after last vaccine. Tumor tissue: baseline, Week 3, and following timing will be performed according to subject's condition.]
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.

Secondary Outcome Measures

Progression Free Survival (PFS) [2 years]
PFS is defined as the time from TP53-EphA-2-CAR-DCs infusion to documented disease progression or death.
Overall Survival (OS) [2 years]
OS is defined as the time from TP53-EphA-2-CAR-DCs infusion to the date of death.
Time to response (TTR) [2 years]
TTR is defined as the time from TP53-EphA-2-CAR-DCs infusion to first assessed CR or PR by investigators and based on the iRECIST criteria.
Duration of response (DOR) [2 years]
DOR is defined as the time from objective response (OR) until documented tumor progression date among responders.
Number and copy number of TP53-EphA-2-CAR-DCs [Peripheral blood: baseline, weekly before Week 9, prior to each vaccination after Week 9 until last vaccination and 1 year after last vaccination. Tumor tissue: baseline, Week 3, and following timing will be performed according to subject's condition.]
Number and copy number of TP53-EphA-2-CAR-DCs were assessed by the number in peripheral blood and tumor tissue.
The level of cytokines in serum [Peripheral blood: baseline, weekly before Week 9, prior to each vaccination after Week 9 until last vaccine and 1 year after last vaccine.]
The cytokines mainly include IL-1, IL-2, IL-6, IL-8, IL-10, IL-12 (p70), TNF-α

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

1. Age 18-75 (inclusive). 2. ECOG performance status ≤2 and Estimated life expectancy of more than 3 months.

Local advanced/metastatic solid tumors or R/R lymphomas confirmed by histopathology or cytology with documentation of tumor EphA2 positive (≥20%) and TP53 mutation (R273H or R175H or R248Q or R249S) within 6 months prior to screening. The second malignancy is allowed.
No clinical response to standard frontline therapy or no standard therapy exists for solid tumors. Relapse after treatment with ≥2 lines systemic therapy or refractory disease for lymphomas. Patients who have declined standard therapy or have no access to standard therapy may be enrolled and the reasons for a lack of access need to be documented. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed, regardless of the level of PD-1/PD-L1 expression, dMMR and TMB.
At least one measurable lesion at baseline per RECIST version 1.1 or Lugano response criteria 2014.
Adequate organ function as defined by the following criteria: ANC ≥1000 cells/μL; Platelet count ≥80,000/μL; Hemoglobin ≥8.0 g/dL (hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions); 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.
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.
Willing to complete all scheduled visits and assessments at the institution administering the therapy.
Able to read, understand and provide written informed consent.

Exclusion Criteria:

Inclusion Criteria:

Age 18-75 (inclusive).
ECOG performance status ≤2 and Estimated life expectancy of more than 3 months.
Local advanced/metastatic solid tumors or R/R lymphomas confirmed by histopathology or cytology with documentation of tumor EphA2 positive (≥20%) and TP53 mutation (R273H or R175H or R248Q or R249S) within 6 months prior to screening. The second malignancy is allowed.
No clinical response to standard frontline therapy or no standard therapy exists for solid tumors. Relapse after treatment with ≥2 lines systemic therapy or refractory disease for lymphomas. Patients who have declined standard therapy or have no access to standard therapy may be enrolled and the reasons for a lack of access need to be documented. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed, regardless of the level of PD-1/PD-L1 expression, dMMR and TMB.
At least one measurable lesion at baseline per RECIST version 1.1 or Lugano response criteria 2014.
Adequate organ function as defined by the following criteria: ANC ≥1000 cells/μL; Platelet count ≥80,000/μL; Hemoglobin ≥8.0 g/dL (hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions); 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.
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.
Willing to complete all scheduled visits and assessments at the institution administering the therapy.
Able to read, understand and provide written informed consent.

Exclusion Criteria:

Having TP53 (R273H or R175H or R248Q or R249S) germline mutation.
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.
Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation.
Evidence of active uncontrolled viral, bacterial, or systemic fungal infection.
Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
Active infection of hepatitis B virus (HBV), or hepatitis C virus (HCV).
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.
Major trauma or major surgery within 4 weeks prior to enrollment.
Previous treatment involving TP53 mutant (R273H or R175H or R248Q or R249S) and EphA2.
Systemic chemotherapy and other intervene within 2 weeks prior to vaccination.
Being participating or withdrew any other trials within 4 weeks.
Any serious underlying medical (eg, pulmonary, renal, hepatic, gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements.
Vaccination within 30 days of study enrollment.
Pregnant, lactating, or breastfeeding females.
Researchers believe that other reasons are not suitable for clinical trials.