This is a single center, first-in cancer-type phase I clinical trial of FT536 for adult patients with recurrent WHO Grade 4 astrocytoma, irrespective of IDH-mutational status, for which a standard of care repeat craniotomy for gross tumor resection at time of first or second recurrence is achievable. Per this treatment schema, FT536 will be administered once intratumorally

This is a single center, first-in cancer-type phase I clinical trial of FT536 for adult patients with recurrent WHO Grade 4 astrocytoma, irrespective of IDH-mutational status, for which a standard of care repeat craniotomy for gross tumor resection at time of first or second recurrence is achievable.

Per this treatment schema, FT536 will be administered once intratumorally. FT536 is an allogeneic natural killer (NK)-cell immunotherapy produced from a clonal master human induced pluripotent stem cell (iPSC) line with the following four engineered elements: a) deletion of the gene encoding CD38 (i.e., CD38 knockout); b) expression of the MICA and MICB (MICA/B) chimeric antigen receptor (CAR); c) high-affinity, non-cleavable CD16 receptor; and d) an interleukin (IL)-15/IL15 receptor alpha fusion protein.

Current neuro-oncology professional census accepts the practice of a 2-stage neurosurgical intervention when there are radiographic changes concerning for recurrent cancer. First, the region of radiographic concern is biopsied to histologically confirm recurrence versus pseudoprogression. If intraoperative pathology is consistent with recurrence, then FT536 will be injected with a total volume of 1 mL infused along the biopsy tract into the residual enhancing portion, but also into the nonenhancing portions if safe and feasible per the discretion of the operating neurosurgeon. Occurring 7- 14 days later, the patient will undergo maximum safe surgical resection and a post-operative safety MR brain imaging will be performed to assess neurosurgical outcome and potential local toxicity.

Inclusion Criteria:

• Histologically confirmed WHO Grade 4 astrocytoma from archival tissue. IDH mutation status and MGMT promoter methylation status will not limit candidacy but needs to be known.
• Evidence of first or second cancer recurrence/ progression by magnetic resonance imaging (MRI) for which a gross tumor resection (GTR) is feasible as determined by the primary investigator in concordance with the study-affiliated neurosurgeon.
• Previous completed SOC antitumor treatment including surgery, radiation therapy, and temozolomide +/- Optune/ Tumor Treatment Fields (TTF).
• No concurrent alternative curative therapy, including use of TTF.
• Able to undergo standard MRI scans with contrast agent throughout the course of the study.
• ≥ 18 years and ≤ 75 years of age at the time of consent.
• Karnofsky performance status ≥70.
• Must be completely off or on a dose of dexamethasone 2mg daily or less with stable neurological function at the time of enrollment.
• Adequate organ function within 14 days of study treatment start as defined in Section 4.1.9 of the protocol.
• Participants of childbearing potential (POCBP) or with partners of childbearing potential must use a highly effective form of contraception from the time of the screening visit until at least 3 months after the dose of FT536.
• Must agree to and sign the consent for the companion Long-Term Follow-Up study (CPRC# 2021LS077).
• Voluntary written consent prior to the performance of any research related procedures.
• Agree to stay in the Twin Cities metropolitan area (i.e. within a 45-minute drive of the UMN) from the time of biopsy through hospital discharge following completion of the planned craniotomy.

Exclusion Criteria:

• Clinically significant increased intracranial pressure (e.g., impending herniation or requirement for immediate palliative treatment) or uncontrolled seizures or any other situation requiring urgent neurosurgical intervention.
• History of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) or with features suggestive of MDS/ AML.
• Radiographic evidence of leptomeningeal disease.
• Received prior treatment with bevacizumab or any other cellular therapy available on or off a clinical trial.
• Non-malignant CNS disease such as CNS vasculitis or neurodegenerative disease.
• Prior or current GammaTile, Gliadel wafer use, or other implanted therapeutic agent or photodynamic therapy.
• Any known condition that requires systemic immunosuppressive therapy - inhaled and topical steroids are permitted.
• Pregnant or breastfeeding. Menstruating POCBP must have a negative pregnancy test within 14 days before the planned biopsy. Patient must agree to use highly effective method of birth control from the time of the screening visit until at least 3 months after the dose of FT536.
• Known seropositive for HIV or known Hepatitis B or C infection with detectable viral load by PCR.
• Prior history of malignancy within 5 years of enrollment other than basal or squamous cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ carcinoma of the breast, or prostate cancer treated with surgery or RT with a prostate specific antigen of <0.01 ng/mL tested within 28 days of trial enrollment.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pec