Methods and compositions for treating cancer
Inventors
Terrett, Jonathan Alexander • Kalaitzidis, Demetrios • DEQUÉANT, Mary-Lee • PADALIA, Zinkal Samir
Assignees
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Publication Number
US-12227763-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Provided herein, in some embodiments, are methods and compositions (e.g., cell compositions) for the treatment of cancer.
Core Innovation
The invention describes engineered T cells for treatment of a subject having cancer that is a solid tumor malignancy expressing CD70. The engineered T cells comprise disrupted TRAC, disrupted 3M, and disrupted CD70, together with a nucleic acid encoding a CAR that binds CD70, wherein the disrupted TRAC gene comprises the nucleic acid encoding the CAR.
The CAR includes an anti-CD70 scFv that binds CD70 and comprises a heavy-chain variable domain (VH) and a light-chain variable domain (VL). The disclosure includes TRAC locus insertion, CD70 knockout CAR T constructs, VH and VL CDR sequences defined by SEQ ID NOs, and a CAR binding domain comprising the amino acid sequence of SEQ ID NO: 46.
The disclosed systems report in vivo efficacy and durability in xenograft models, including ovarian, kidney, lung, pancreatic, renal carcinoma, large renal cell carcinoma tumors, and T-cell lymphoma contexts. Reported outcomes include tumor regression or elimination, reduced solid tumor volume, delayed relapse on rechallenge, long-term persistence, reduced exhaustion markers including PD-1 and LAG3, and improved proliferation, persistence, cytotoxicity, cytokine release, and cell killing potency.
Claims Coverage
The consolidated claim coverage includes treatment of CD70-expressing solid tumor malignancy by administering engineered T cells with three specific gene disruptions and a CD70-binding CAR. Across the provided claims, the inventive features are the disrupted TRAC gene that comprises the CAR-encoding nucleic acid, disrupted 3M, disrupted CD70, and the CD70-binding CAR itself, with dependent claims adding solid tumor types, tumor-volume reduction, and defined CAR sequence details.
Multi-gene disrupted engineered T cells for CD70-expressing solid tumors
Administering to a subject a population of cells comprising engineered T cells comprising a disrupted TRAC gene, a disrupted 3M gene, and a disrupted CD70 gene, and a nucleic acid encoding a CAR that binds CD70, wherein the disrupted TRAC gene comprises the nucleic acid encoding the CAR; wherein the subject has cancer that is a solid tumor malignancy and expresses CD70.
Car treatment of specified solid tumor malignancies
The method wherein the cancer is a solid tumor malignancy selected from ovarian, pancreatic, kidney, lung, or intestinal tumors.
Reducing solid tumor volume with an amount effective
Administering the population of cells to a subject in an effective amount to reduce the volume of a solid tumor malignancy in the subject.
Anti-CD70 scFv CAR binding domain with VH and VL
A CAR whose single-chain antibody fragment (scFv) binds CD70, wherein the CAR includes an anti-CD70 scFv with a heavy-chain variable domain (VH) and a light-chain variable domain (VL).
Specified VH/VL CDR sequences for the anti-CD70 scFv
A heavy chain V_H that includes specified CDR1, CDR2, and CDR3 sequences (SEQ ID NOs: 68, 70, and 72) and a light chain V_L that includes specified CDR1, CDR2, and CDR3 sequences (SEQ ID NOs: 62, 64, and 66).
CD70-binding CAR amino acid sequence defined by SEQ ID
A CAR whose binding domain comprises the amino acid sequence of SEQ ID NO: 46 that binds CD70.
The consolidated claim coverage centers on engineered T cells with disrupted TRAC, disrupted 3M, and disrupted CD70 for treating CD70-expressing solid tumor malignancy. The dependent claims further specify solid tumor examples, a tumor-volume reduction outcome, and CAR structure defined by anti-CD70 scFv VH/VL composition, SEQ ID-defined CDRs, and SEQ ID NO: 46.
Stated Advantages
Reduces the volume of a solid tumor malignancy in the subject.
Prevents tumor growth on re-challenge.
Improved proliferation and persistence
Reduced exhaustion and apoptosis
Enhanced cytotoxicity at low effector:target ratios and serial rechallenge durability
Rescue of PD-1 knockout phenotypes under PD-L1 challenge
In vivo tumor regression with serial rechallenge and long-lasting efficacy
Delayed relapse in rechallenge tumor outcomes
Long-term persistence of engineered cells in vivo, up to at least 57 days
Improved potency in anti-BCMA settings when CD70 is disrupted, even without an anti-CD70 CAR
Cytokine dependency and lack of proliferation without cytokines/serum as an off-target safety proxy
Reduction of exhaustion markers including PD-1 and LAG3
Improved functional effects including cytokine release and cell killing potency
Documented Applications
Treating a subject with cancer that is a solid tumor malignancy expressing CD70 by administering engineered T cells comprising disrupted TRAC, disrupted 3M, and disrupted CD70 together with a CD70-binding CAR.
Treating CD70-expressing solid tumor malignancies selected from ovarian, pancreatic, kidney, lung, or intestinal tumors.
Reducing solid tumor volume in a subject through administration of an amount effective to reduce tumor volume.
Treatment of solid tumor malignancy expressing CD70, with in vivo tumor regression described in renal carcinoma and BCMA tumor xenograft models
Serial rechallenge and long-lasting efficacy in the described in vivo tumor regression contexts
In vivo efficacy and durability of genome-edited anti-CD70 CAR T cells in xenograft models including A498 renal carcinoma, large renal cell carcinoma tumors, SKOV-3 ovarian carcinoma, NCI-H1975 lung carcinoma, Hs766T pancreatic carcinoma, and HuT78 T-cell lymphoma, including rechallenge experiments
Rechallenge tumor experiments demonstrating delayed relapse and durable outcomes
Use in anti-BCMA CAR contexts showing that CD70 knockout can increase potency even without an anti-CD70 CAR
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