Phase I, open label, prospective, single-center, non-randomized, dose escalation clinical trial aiming to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of systemic transduced donor-derived NKG2D-CAR memory T cell infusions (Arm A), and of dual treatment, with both systemic and locally transduced donor-derived NKG2D-CAR memory T cell infusions (Arm B).
Childhood cancer is considered a rare disease based on prevalence. Despite this, in developed countries, cancer is the most common cause of disease-related death in the pediatric population. Sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin representing around 10% of pediatric cancers. For patients with standard-risk and localized disease, survival is 70-80%. However, for those patients with high-risk disease, or those who relapse or develop metastases, the survival rate is only 30%. Current treatment consisting in local surgery, radiotherapy and poly-chemotherapy remains ineffective in advanced stages or relapse and is associated with acute and chronic adverse effects which compromise survival and quality of life. Thus, there is an urgent need to find new therapeutic alternatives in order to improve the outcome in sarcoma patients. Different groups have described the importance of NKG2D receptor and NKG2D ligands (NKG2DL) in sarcoma immunosurveillance. Tumor cells are recognized and eliminated by the immune surveillance system. A master key receptor called NKG2D is critical to induce cancer control. Recently, this group has published how this receptor can recognize and target most childhood cancers including sarcoma. Although different cells from the surveillance system possess this receptor, cancer cells can block their ability to recognize and eliminate the tumor cells. NKG2D CAR receptor induces tumor-specific lysis, is safe to normal cells and provides effector cells the ability to bypass the mechanisms of resistance induced by tumor cells. In the present study the investigators aim to analyze the safety of an NKG2D-CAR T cell therapy in pediatric, adolescent and young adult (AYA) patients suffering from advanced sarcoma. In a recent preclinical study developed by this group, the investigators demonstrated the efficacy and safety of an NKG2D-CAR T cell-based therapy for osteosarcoma. Furthermore, in this hospital, NKG2D-CAR T cells have been already produced in a GMP-environment and infused in two pediatric patients as compassionate use, and no signs of treatment-related toxicity have been observed. In the present study, the investigators aim to develop a dose escalation Phase I trial of NKG2D chimeric antigen receptor-T cells (NKG2D-CAR T) to assess the safety and clinical activity in pediatric patients with advanced sarcoma. This clinical trial proposal is the continuation of a previous research project funded by the Asociación Española Contra el Cáncer (AECC) in 2016, which was the first AECC funded project on CAR T cell therapy in children with metastatic disease.
Patients will be allocated in two groups: Arm A and Arm B. Both groups will receive an intravenous infusion of NKG2D-CAR memory T cells. Additionally, patients on Arm B will receive an intratumoral dose of NKG2D-CAR memory T cells (in accessible primary tumor and metastases). The distribution of patients on one arm or other will depend on their clinical characteristics described in the inclusion/ exclusion criteria. All patients will receive lymphodepleting chemotherapy prior to the infusion of NKG2D-CAR memory T cells according to the usual clinical practice in our center. Some patients will also receive low dose radiotherapy prior to infusion.
Hospital Universitario La paz
Madrid, Spain
RECRUITINGSafety: Dose-limiting toxicity (DLT) of NKG2D-CAR memory T cells
1. Any grade 3 or higher toxicity with an attribution of definitely or probably related to the infusion of the NKG2D CAR-T cells with the exception of Grade 3 fever and immediate hypersensitivity reactions occurring within 2hours of cell infusion that are reversible to a Grade 2 or less within 24 hours of cell administration with standard therapy; 2. Any lower grade toxicity that increases to a grade 3 or higher as a direct result of the NKG2D CAR-T cell infusion.
Time frame: During the study treatment, until 28 days after the last study iv treatment administration
Safety: Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells
The highest dose level if no Dose-limiting toxicitys are observed
Time frame: During the study treatment, until 28 days after the last study iv treatment administration
Response rate
This outcome will be evaluated by Immune-Related Response Criteria (iRECIST) v1.1. The efficacy will be measured by objective response rate (ORR) at D60 in both arms, which includes Complete Response (CR) and Partial Response (PR) based on Immune-Related Response Criteria iRECIST v1.1.
Time frame: At day 60 after the treatment
Rate of NKG2D-CAR T cells persistence in peripheral blood
Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in peripheral blood at screening and then starting from D1.
Time frame: During 12 months after the treatment
Rate of NKG2D-CAR T cells persistence in the tumor and metastasis site
Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in the tumor samples at biopsy times (D21 and D60).
Time frame: 21 and 60 days after the treatment
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Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Rate of NKG2DL positive expression on primary sarcoma samples
Number of Arm A and Arm B subjects with persistence of NKG2D-CAR T cells in peripheral blood at D21 and D60.
Time frame: 21 and 60 days after the treatment
Cytokine determination in the serum of patients
Obtain primary patient-derived cancer cells from accessible sarcomas
Time frame: During 12 months after the treatment
Analysis of patient peripheral blood immune cell subpopulations
Identify the immune cell phenotypes linked to CAR-T expansion and response provides an opportunity to understand the mechanisms of CAR-T success and craft approaches to improve CAR-T activity. The changes in cell differentiation stages and exhaustion markers of immune populations will be done by spectral flow cytometry.
Time frame: 21 and 60 days after the treatment
Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPS 1-3) in primary sarcoma samples and DNA methylation profile of NKG2D-T cells before and after infusion.
Analyze the DNA methylation profile of MICA, MICB and ULBP1-3 genes in primary sarcoma samples from D0, D21 and D60, by pyrosequencing techniques.
Time frame: 21 and 60 days after the treatment
Evaluate the presence of soluble NKG2DL and ANTI-MICA antibodies in the serum of patients under therapy
The presence of anti-MICA antibodies will be determined in the serum of patients obtained at different times using LABScreen assay by Luminex Technology (LABScreen TM MICA and LSA-MIC single antigen, One Lambda and Diagnostica Longwood, respectively).
Time frame: During 60 days after the treatment