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).
Age: ≤ 40 years at the time of recurrence or progression with any type of sarcoma that has recurred or not responded to standard therapy and is deemed incurable by standard therapy.
If the patient doesn´t have adequate accessible tumor for biopsy (at least 1 cm diameter).
Procedures employed to acquire biopsies for tumor lysates will be limited to percutaneous needle or core biopsies, thoracoscopic excision or open biopsies of readily accessible lesions. Pulmonary lesions may be biopsied but extensive surgery such as thoracotomy or laparotomy should not be employed.
Patients who require biopsy should not be enrolled if in the opinion of the principal investigator (PI), the tumor site places the patient at substantial related risk from the biopsy procedure.
Enrolled in another treatment protocol.
Cardiac disorder defined as LVFE < 45% determined by ECHO.
Human Immunodeficiency Virus (HIV) positive test.
Presence of active or prior CMV, EBV, hepatitis B or C as indicated by serology.
Parallel
NKG2D-CAR memory T cell
Other interventionPatients 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.
Safety: 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.
Safety: Maximum Tolerated Dose (MTD) of NKG2D-CAR memory T cells
The highest dose level if no Dose-limiting toxicitys are observed
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.
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.
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).
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.
Cytokine determination in the serum of patients
Obtain primary patient-derived cancer cells from accessible sarcomas
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Antonio Pérez Martínez
Lead sponsor
Instituto de Investigación Hospital Universitario La Paz
Sponsor institution
