Trial to evaluate CAR-T NKG2D CAR cell infusions in patients with advanced sarcoma

Prior treatment

• Evidence of untreated and active infection or clinically significant systemic illness: o Cardiac disorder defined as LVFE < 45 % determined by ECHO. o Human Immunodeficiency Virus (HIV) positive test. o Presence of active or prior CMV, EBV, hepatitis B or C as indicated by serology. o Any significant pulmonary, hepatic or other organ dysfunction.
• Chronic corticosteroid dependence (except replacement therapy).

Other illness

• Medical history of epilepsy.
• Any other condition that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial.

Other

• Enrolled in another treatment protocol.
• Evidence of any toxicity grade ≥ 4 (according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0).
• Pregnant or lactating women.

• 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.
• Patient or patient's legal representative, parent(s), or guardian able to provide written informed consent.
• Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the infusion. Male partner should use a condom.
• Positive NKG2DL expression in sarcoma samples. Ideally, they should have centralized histological verification of NKG2DL expression in sarcoma samples (positive expression is defined as at least 2+ expression (0-4+ scale) in >50 percent of the tumor cells using anti-MICA and or anti-ULBP2). Patients will undergo biopsy following enrollment to obtain tissue to assess NKG2DL expression, with the following restrictions: o If the patient does not have an adequate accessible tumor for biopsy (at least 1 cm diameter). o 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. o 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. In patients that fulfill any of these restrictions, when adequate archived tissue is available, this may be utilized to assess NKG2DL expression.
• Patients must have either measurable or evaluable tumor.
• The tumor must be accessible for intralesional administration of CAR T cells (only in ARM B).
• Life expectancy of at least 10 weeks in opinion of the principal investigator (PI).
• Lansky (age <16 years) or Karnofsky (age >=16 years) score of 50 or greater.
• Patients must have recovered from the acute toxic effects of all prior anticancer therapy (including chemotherapy and radiotherapy).
• Adequate bone marrow function defined by an absolute neutrophil count (ANC) of >/= 1.000/μL, platelet count of >/= 30.000/μL and hemoglobin of >/= 9.0 g/dl, and absence of a regular red blood cell and platelet transfusion requirement.
• Patients should have a normal hepatic function with a total bilirubin <2 times the upper limit of normal and serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) < 2 times the upper limit of normal, and adequate renal function as defined by a serum creatinine ≤ 1.5 upper limit of normal.