IL-8 Receptor Modified Patient-Derived Activated CD70 CAR T Cell Therapy in Adults With Brain Metastases

Adult patients with newly diagnosed or recurrent/progressive brain metastases will be screened. Consented patients will undergo screening procedures followed by tumor biopsy/surgery if clinically indicated, and may receive treatment for brain metastases, which include whole brain radiation therapy (WBRT), SRS treatment for new lesion(s) (SRS is permitted for recurrent disease only for newly developed brain lesion(s). Enrollment and administration of standard-of-care treatment will be coordinated such that each subject will not receive the CAR T-cell product until the preceding subject has completed the required 28-day dose-limiting toxicity observation period.

After enrollment, patients will be evaluated for cellular therapy suitability and undergo cell collection for the generation of 8R-70CAR T cells before initiation or up to two cycles while receiving standard-of-care chemoradiation. As part of screening, CD70 protein will be confirmed on primary tumor or lymph nodes biopsy. If the patient is eligible, they will receive FDA-approved standard of care therapy for their primary disease as a 2-4 cycles bridge while the 8R-70 CAR T cells are being manufactured. Following completion of standard of care therapy and prior to cellular therapy, patients will be evaluated to confirm disease stability. MRI of brain and CT imaging will be obtained within 28 days prior to CAR administration for disease staging.

If radiographic or clinical progression is identified, the treating physicians may consider initiating therapy for the primary disease prior to CAR administration. Upon completion of the additional line of therapy, eligibility for CAR administration will be reassessed at the discretion of the treating physicians based on overall clinical stability and disease control.

A single dose of 8R-70CAR T cells will be administered IV injection 2 to 6 months after study enrollment. Administration will be conducted in the hospital so the patient can be monitored for infusion-related toxicities.

After hospital discharge, patients will be required to remain within a 1-hour drive of UF Health for at least two weeks following infusion for safety monitoring. Patients receiving study treatment will be required to have a caregiver and advised to avoid driving for two weeks following product administration.

Patients will have post-infusion follow-up visits in the UF Health clinic 7 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, and 12 weeks after CAR T administration.

Patients who continue to receive care at the University of Florida will be seen at the UF Health Neuro-oncology/Neurosurgery clinic every 2 months, for the first 12-24 months, then every 3 months for 12 months, then every 4 months or when clinically indicated for physical \& neuro exam, interim medical history, until progressive disease and every 6 months thereafter.

Patients who transfer their care to an outside provider/institution will be contacted by phone at 3, 6, 12 months, and every 6 months thereafter for follow-up.

All patients who receive the 8R-70 CAR T cells investigational product will continue to be followed until death. Patients will also be followed up to 15 years in accordance with the guidance "Gene Therapy Clinical Trials - Observing Subjects for Adverse Events" to identify and mitigate the potential long-term risks to the patients receiving the investigational product.

• Ex-Vivo expanded autologous IL-8 receptor (CXCR2) modified CD70 CAR (8R-70CAR) T cells (Biological), also known as 8R-70 CAR T Cells: Single dose of 8R-70CAR T cells administered IV
• CD70 IHC assay (Device): CD70 expression will be assessed during screening using available tumor tissue obtained as part of routine clinical care from the primary tumor, lymph node, or brain metastasis, as applicable. The CD70 IHC result will be used to determine study eligibility. CD70 expression will be evaluated using an investigational immunohistochemistry (IHC) assay.

Primary outcomes

• Number and percentage of participants with dose-limiting toxicities after receiving 8R-70CAR T-cell therapy [28 days post-infusion]: Safety is defined as ≤ 1 DLT out of 6 patients is observed at the 1x10\^8 cells/Kg dose. Dose-Limiting toxicity (DLT) will be defined as any adverse event attributable (possible, probable, or definite) to the administration of 8R-70CAR T cells and occurring from the time of infusion through 28 days post-infusion. Safety variables and variables that define the DLTs will be summarized using descriptive statistics by dose level. Number and percentage of patients with DLTs and its 95% confidence interval (CI) will be estimated based on the exact binomial distribution by dose level.
• Proportion of participants who receive an infusion of 8R-70CAR T-cell therapy [enrollment up to 10 weeks]: Feasibility will be defined as the ability to infuse 8R-70CAR T-cell safely in 66.7 % of enrolled patients (patients who signed consent and were deemed eligible for the study).

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Histological confirmation of primary cancers
* Histologic confirmation of CD70 on primary tumor, lymph node, or BM biopsy CD70-positive tumor expression confirmed by the investigational CD70 IHC assay defined as CD70 immunoreactivity in ≥ 5% of tumor cells at any staining intensity.
* At least one recurrent or progressive metastatic lesion or new metastatic lesion(s).
* KPS ≥ 70.
* 18 years or older.
* Adequate bone marrow and organ function as defined below:

  * CBC with differential with adequate bone marrow function as defined below:
  * Absolute neutrophil count (ANC) ≥ 1000 cells/mm3.
  * Platelet count ≥ 75,000 cells/mm3.
  * Hemoglobin ≥ 9 g/dl. (use of transfusion or other intervention to achieve Hgb ≥ 9 g/dl is acceptable.)
* Adequate renal function as defined below:

  * BUN ≤ 25 mg/dl
  * Creatinine ≤ 1.7 mg/dl
* Adequate hepatic function as defined below:

  * Bilirubin ≤ 2.0 mg/dl
  * ALT ≤ 5 times institutional upper limits of normal for age
  * AST ≤ 5 times institutional upper limits of normal for age
* A diagnostic contrast-enhanced brain MRI must be performed within 28 days prior to study enrollment.
* For females of childbearing potential, a negative serum pregnancy test at enrollment.
* Women of childbearing potential (WOCBP) must be willing to use an acceptable contraceptive method to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
* Males with female partners of childbearing potential must agree to practice adequate contraceptive methods throughout the study and should avoid conceiving children for 24 weeks following the last dose of the study drug.
* Ability of the patient to understand and willingness to sign an IRB approved written informed consent document.
* Steroid dose equivalent to dexamethasone dose of ≤ 6mg daily at the time of enrollment.
* Patients treated on any other investigational therapy must discontinue that treatment prior to study entry.

Exclusion Criteria:

• Known immunosuppressive disease or human immunodeficiency virus (HIV) infection.

Rationale: The need to exclude patients with an immunosuppressive disease or human immunodeficiency virus infection is necessary because the management of potential toxicities from the study drug may involve treatment that is significantly immunosuppressive.

* Participant has ongoing toxicity ≥ grade 2 per the CTCAE version 5.0 considered clinically significant and in the opinion of the investigator, attributable to prior antineoplastic therapies.
* Participant has received any chemotherapy or other immunotherapy within 14 days prior to the first dose of study intervention.
* Severe, active co-morbidity, defined as follows:

  * Unstable angina and/or congestive heart failure requiring hospitalization.
  * Transmural myocardial infarction within the last 6 months.
  * Acute bacterial or fungal infection requiring intravenous antibiotics.
  * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization.
  * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
  * Patients with an autoimmune disease requiring medical management with immunosuppressants.
  * Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.
* Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant.

• Maryam Rahman, MD, Principal investigator, University of Florida