Trial Title:
CAR-DC Vaccine and ICIs in Local Advanced/Metastatic Solid Tumors
NCT ID:
NCT05631899
Condition:
Solid Tumor, Adult
EphA2 Overexpression
KRAS G12V
KRAS G12C
KRAS G12D
Conditions: Official terms:
Neoplasms
Cyclophosphamide
Ipilimumab
Albumin-Bound Paclitaxel
Paclitaxel
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antibodies, Blocking
Conditions: Keywords:
Local Advanced/Metastatic
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
KRAS-EphA-2-CAR-DC
Description:
5~10 × 10^6 CAR-DCs per dose will be administered by intravenous injection.
Arm group label:
KRAS-EphA-2-CAR-DC
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody
Intervention type:
Drug
Intervention name:
Abraxane
Description:
Intravenous abraxane 125 mg/m^2/day on day-5.
Arm group label:
KRAS-EphA-2-CAR-DC
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody
Other name:
Abraxane Injectable Product
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Intravenous cyclophosphamide 300 mg/m^2/day on day -4.
Arm group label:
KRAS-EphA-2-CAR-DC
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody
Other name:
Cyclophosphamide for Injection
Intervention type:
Drug
Intervention name:
Anti-PD-1 antibody
Description:
Intravenous anti-PD-1 antibody 200 mg/day.
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody
Other name:
PD-1 blocking antibody
Intervention type:
Drug
Intervention name:
Anti-CTLA4 Monoclonal Antibody
Description:
Intravenous anti-CTLA4 antibody 1 mg/kg/day
Arm group label:
KRAS-EphA-2-CAR-DC plus anti-PD-1 antibody and anti-CTLA4 antibody
Other name:
Ipilimumab
Summary:
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.
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 solid tumors.
Therefore, we designed an autologous CAR-DC vaccine engineered with anti-EphA2 CAR and
KRAS mutant peptide (KRAS-EphA-2-CAR-DC) , which can suppress the growth of tumors
expressing the correlated KRAS mutant in animal models. In addition, the combination of
the immune checkpoint 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 KRAS-EphA-2-CAR-DC combined with anti-PD-1 antibody/anti-CTLA4
antibody in patients with local advanced/metastatic solid tumors.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Biotherapeutic Department of Chinsese PLA Gereral Hospital
Address:
City:
Beijing
Zip:
100853
Country:
China
Status:
Recruiting
Contact:
Last name:
Weidong Han, PH.D
Phone:
010-66937463
Phone ext:
+86
Email:
hanwdrsw69@yahoo.com
Contact backup:
Last name:
Yang Liu, M.D
Phone:
010-66939460
Phone ext:
+86
Email:
liuyang301blood@163.com
Start date:
April 3, 2023
Completion date:
December 30, 2026
Lead sponsor:
Agency:
Chinese PLA General Hospital
Agency class:
Other
Collaborator:
Agency:
Zhejiang University
Agency class:
Other
Source:
Chinese PLA General Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05631899
