TCR1188-ABC Cells in KRAS-mutated Cancers

This is a Phase I, open-label dose finding study to assess the safety, manufacturing feasibility, and preliminary efficacy of TCR1188-ABC cells in patients with KRAS-mutated cancers. Initially, patients with KRAS G12V mutation positive metastatic pancreatic adenocarcinoma, cholangiocarcinoma, colorectal cancer, or non-small cell lung cancer (NSCLC) will be targeted for participation. Up to 4 total dose levels will be evaluated using a 3+3 dose escalation design.

Biological: TCR1188-ABC cells. TCR1188 modified, base-edited autologous CD4+ and CD8+ T cells expressing TCR1188 and a scFv fragment specific to ILT4 (LILRB2) as a Single infusion on Day 0

Drug: Fludarabine + Cyclophosphamide combination. Fludarabine: 30 mg/m2/day x 4 days (Day -7 to -4) Cyclophosphamide: 600mg/m2/day x 3 days (Day -7 to -5)

Drug: Tocilizumab. Single administration of 8mg/kg on Day 2 (+3d)

Dose level -1 (experimental): 1.11 x 10\^8 TCR1188-ABC cells

Dose level 1 (experimental): 3.33 x 10\^8 TCR1188-ABC cells

Dose level 2 (experimental): 1 x 10\^9 TCR1188-ABC cells

Dose level 3 (experimental): 3 x 10\^9 TCR1188-ABC cells

Number of Subjects with treatment related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) V6.0. Type, frequency, severity, and attribution of adverse events Time frame: Up to 15 years following TCR1188-ABC cell administration.

Occurrence of dose-limiting toxicities (DLTs). Type, frequency, severity, and attribution of dose limiting adverse events as defined by the protocol Time frame: Up to 28 days following TCR1188-ABC cell administration.

Identification of the maximum tolerated dose (MTD). The highest dose at which 0 or 1 DLT occurs in 6 DLT-evaluable subjects will be declared the MTD. Time frame: 28 days post-TCR1188-ABC cell infusion.

Occurrence of product release failures. Time frame: 3 months.

Proportion of TCR1188-ABC cells that fail to meet the protocol-defined dose. Time frame: 3 months.

Overall Response Rate (ORR). Time frame: Up to 12 months following TCR1188-ABC cells administration.

Duration of Response (DOR). Time frame: Up to 15 years following TCR1188-ABC cell administration.

Progression-Free Survival (PFS). Time frame: Up to 15 years following TCR1188-ABC cell administration.

Overall Survival (OS). Time frame: Up to 15 years after last TCR1188-ABC cells administration.

Inclusion Criteria: 1. Patients ≥ 18 years of age 2. Patients with one of the following diagnoses: 1. Histologically confirmed metastatic pancreatic adenocarcinoma or cholangiocarcinoma 2. Histologically confirmed metastatic colorectal cancer 3. Histologically confirmed metastatic non-small cell lung cancer 3. HLA-A\*11:01 positive as confirmed by a CLIA certified laboratory. 4. KRAS G12V mutation positive disease as confirmed on tissue, blood, or plasma by next generation sequencing by a CLIA certified laboratory. 5. Received prior treatment for their primary malignancy as follows: 1. Pancreatic Cancer/Cholangiocarcinoma Patients: At least one prior line of standard of care therapy for advanced stage disease. For pancreatic cancer patients, this must include a gemcitabine or fluorouracil (5 FU)-based regimen. 2. Colorectal Cancer Patients: At least three prior lines of standard of care therapy for advanced stage disease. Prior treatment must include all of the following unless the patient was ineligible for a specific therapy type: i). a fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimen, ii). an anti-vascular endothelial growth factor (VEGF) agent, and iii). regorafenib, trifluridine-tipiracil, or fruquintinib. Patients with microsatellite instability-high (MSI-H) disease must also have received, or be ineligible for, prior treatment with an immune checkpoint inhibitor. 3. Non-Small Cell Lung Cancer Patients: At least one prior line of standard of care therapy for advanced stage disease. 6. Evidence of radiographically detectable disease within 8 weeks of physician-investigator confirmation of eligibility. 7. Adequate organ function within 4 weeks of eligibility confirmation by a physician-investigator defined as: 1. Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50 cc/min per the Cockcroft-Gault Equation; Patient must not be on dialysis. 2. ALT/AST ≤ 5 x ULN (patients with liver metastases) or ALT/AST ≤ 2.5 x ULN (patients without liver metastases) 3. Total bilirubin ≤ 1.5 mg/dL x ULN, unless the subject has Gilbert's syndrome (if so, direct bilirubin must be ≤ 2.0 mg/dL x ULN) 4. Left Ventricle Ejection Fraction (LVEF) ≥ 50% confirmed by ECHO/MUGA 5. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air 8. Patients must have adequate hematologic reserve within 4 weeks of eligibility confirmation by a physician-investigator and must not be dependent on …

Enrollment: 30 participants (estimated).