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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
9
5\~10 × 10\^6 CAR-DCs per dose will be administered by intravenous injection.
Intravenous abraxane 125 mg/m\^2/day on day-5.
Intravenous cyclophosphamide 300 mg/m\^2/day on day -4.
Intravenous anti-PD-1 antibody 200 mg/day.
Intravenous anti-CTLA4 antibody 1 mg/kg/day
Biotherapeutic Department of Chinsese PLA Gereral Hospital
Beijing, Beijing Municipality, China
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Progression Free Survival (PFS)
PFS is defined as the time from KRAS-EphA-2-CAR-DCs infusion to documented disease progression or death.
Time frame: 2 years
Overall Survival (OS)
OS is defined as the time from KRAS-EphA-2-CAR-DCs infusion to the date of death.
Time frame: 2 years
Time to response (TTR)
TTR is defined as the time from KRAS-EphA-2-CAR-DCs infusion to first assessed CR or PR by investigators and based on the iRECIST criteria.
Time frame: 2 years
Duration of response (DOR)
DOR is defined as the time from objective response (OR) until documented tumor progression date among responders.
Time frame: 2 years
Number and copy number of KRAS-EphA-2-CAR-DCs
Number and copy number of KRAS-EphA-2-CAR-DCs were assessed by number in peripheral blood and tumor tissue.
Time frame: Peripheral blood samples are collected on days 0, 3, 7, 10, 22, the day before each vaccination until last vaccination and 1 year after last vaccine. Tumor tissues are collected at baseline, the day before Week 5, and after combination.
The level of cytokines in serum
The cytokines mainly include IL-1, IL-2, IL-6, IL-8, IL-10, IL-12 (p70), TNF-α
Time frame: Peripheral blood samples are collected on days 0, 3, 7, 10, 22, the days before each vaccination until last vaccination and 1 year after last vaccine. Tumor tissues are collected at baseline, the day before Week 5, and after combination.
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