Phase I/II study of adoptive immunotherapy for advanced MUC1\* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which are specific for a cleaved form of MUC1 (MUC1\*).
Recent trials have demonstrated that chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) specific for the CD19 molecule can mediate marked tumor regression in a subset of patients with advanced acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). It would be ideal to extend CAR-T cell therapy to common epithelial cancers. However, this poses several challenges, including the identification of molecules expressed on tumor cells that can be targeted safely with CAR-T cells. Minerva Biotechnologies has developed a CAR T product (huMNC2-CAR44 or huMNC2-CAR22) that targets the extra cellular domain of the cleaved form of MUC1 (called MUC1\*), which is the form of MUC1 that functions as a growth factor receptor and is present on large percentage of solid tumors, including breast tumors. The antibody targeting head of huMNC2-CAR44 or huMNC2-CAR22 specifically recognizes a cancerous form of MUC1\* and does not bind to another form of cleaved MUC1 that is present on some normal tissues that also have a rapid turnover. To be clear, patients will receive either huMNC2-CAR44 or huMNC2-CAR22, but not a combined product. The huMNC2-CAR44 product consists of autologous T cells that are isolated from cancer patients, transduced with a proprietary lentiviral vector backbone manufactured under cGMP and containing sequences for a human CD8 alpha leader sequence, humanized MNC2-scFv (MUC1\* targeting head), portions of human CD8 hinge and transmembrane domains, and human 4-1BB and human CD3-zeta costimulatory domains. The huMNC2-CAR44 transduced T cells are antigen-stimulated in vitro, with a synthetic MUC1\* extracellular domain peptide. The CAR T cells are then ready for administration to the patient. Alternatively, the CAR T cells can be cryopreserved, then administered to the patient after thaw at bedside. The huMNC2-CAR22 product is comprised of a CD8-α leader sequence, the huMNC2 scFv, a CD28 hinge and transmembrane region, followed by a CD28 co-stimulatory domain and a CD3-ζ signaling domain bearing two Tyrosine to Phenylalanine mutations in each of ITAMs 2 and 3 to minimize CAR T cell exhaustion and increase in vivo persistence. The huMNC2-CAR22 transduced T cells are not antigen-stimulated. The CAR T cells can be cryopreserved, then administered to the patient after thaw at bedside. The investigators propose to evaluate the safety and preliminary anti-tumor activity of adoptively transferred autologous T cells genetically modified to express a CAR that targets MUC1\*, huMNC2-CAR44 or huMNC2-CAR22, in Phase I/II clinical trials in patients with metastatic MUC1\* positive breast cancers.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
69
huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head).
huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head) @ RP2D
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of Adverse Events
To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells for patients with advanced MUC1\* positive breast cancer using CTCAE version 5.0 and Lee criteria.
Time frame: Within 35 days after T cell infusion
In vivo persistence
Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells.
Time frame: Up to 365 days after the T cell infusion
Preliminary Antitumor Activity
Preliminary antitumor activity of the adoptive transfer of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in all patients with measurable tumor prior to T cell transfer by RECIST 1.1
Time frame: Up to 15 years
Antitumor Activity
Determine antitumor activity at MTD/RP2D of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in patients with luminal breast cancer (hormone receptor positive, HER2 negative), HER2 positive breast cancer, and triple negative breast cancer (hormone receptor and HER2 negative) by RECIST 1.1 in expansion cohorts.
Time frame: Up to 15 years
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