Methods for treatment using chimeric antigen receptors specific for B-cell maturation antigen
Inventors
SATHER, Blythe D. • Smith, Eric L. • Tareen, Semih • CHEN, AYE • De Imus, Cyr • HESS, ERIK • OLSHEFSKY, AUDREY • PONKO, STEFAN • STIRNER, MARIANA COTA
Assignees
Memorial Sloan Kettering Cancer Center • Juno Therapeutics Inc
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Publication Number
US-12473345-B2
Publication Date
2025-11-18
Expiration Date
Abstract
Provided herein are adoptive cell therapy methods involving the administration of doses of cells for treating disease and conditions, including certain plasma cell malignancy. The cells generally express recombinant receptors such as chimeric antigen receptors (CARs) specific to B-cell maturation antigen (BCMA). In some embodiments, the methods are for treating subjects with multiple myeloma (MM). Also provided are genetically engineered cells containing such BCMA-binding receptors for uses in adoptive cell therapy.
Core Innovation
The invention relates to treating a subject having or suspected of having relapsed or refractory multiple myeloma by administering engineered T cells comprising a chimeric antigen receptor (CAR). The CAR comprises an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), together with a spacer set forth by SEQ ID NO: 174 or a sequence with at least 95% sequence identity to SEQ ID NO: 174, a transmembrane domain, and an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and a costimulatory signaling region comprising an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.
The CAR antigen-binding domain is defined by VH and VL complementarity determining region (CDR) sequences contained within specified sequence sets, including CDR-H1, CDR-H2, and CDR-H3 sequences set forth in SEQ ID NO: 116 and CDR-L1, CDR-L2, and CDR-L3 sequences set forth in SEQ ID NO: 119 or specified in particular SEQ ID NOS. The disclosure also refers to embodiments with 4-1BB as the costimulatory signaling region and to spacer-encoding nucleic acid sequences containing modified splice donor and/or modified splice acceptor sites.
The document further emphasizes nucleic-acid and CAR-component optimization to reduce or eliminate cryptic splice sites and to apply codon optimization. This optimization is described as achieving high transcribed RNA homogeneity and minimal RNA heterogeneity, and the disclosure includes iterative testing of RNA splicing by RT-PCR and agarose gel electrophoresis during optimization.
The engineered T-cell product is also described in the context of clinical manufacturing and cell quality, including improved cell health, enrichment for central memory and memory T-cell phenotypes, and polyfunctional, robust cytokine-producing cells. The partial content further references pharmaceutical compositions, lyophilized formulations, parenteral administration, and assessment of response and toxicity endpoints in the context of CRS and neurotoxicity.
Claims Coverage
The document contains three independent claims directed to treating relapsed or refractory multiple myeloma using engineered T cells expressing a BCMA-binding CAR. Across the claims, the main inventive features are the defined BCMA-binding VH/VL CDR sequences, the spacer and signaling-region CAR architecture, the prior-therapy and lymphodepletion treatment context, and in one claim a CAR+ T-cell dose range.
BCMA-binding CAR with specified VH/VL CDR sets plus CD3-zeta and costimulatory signaling
Administering a dose of engineered T cells comprising a chimeric antigen receptor (CAR), where the CAR comprises an extracellular antigen-binding domain that binds to BCMA, including a variable heavy chain (VH) with CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 116 and a variable light chain (VL) with CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 119, a spacer set forth by SEQ ID NO: 174 or a sequence with at least 95% sequence identity to SEQ ID NO: 174, a transmembrane domain, and an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and a costimulatory signaling region comprising an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.
Lymphodepleting fludarabine and cyclophosphamide prior to CAR T administration
Prior to the administration, the subject has received a lymphodepleting therapy comprising fludarabine and cyclophosphamide.
Treatment of relapsed or refractory multiple myeloma after selected prior therapies
The subject has relapsed or been refractory to one or more prior therapies selected from among autologous stem cell transplant (ASCT), an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
BCMA-binding CAR with specified VH/VL CDR sequences and CD3-zeta with costimulation
Administering a dose of engineered T cells comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an extracellular antigen-binding domain that binds to BCMA, including a VH comprising CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOS: 97, 101 and 103, respectively, and a VL comprising CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOS: 105, 107 and 108, respectively, a spacer set forth by SEQ ID NO: 174 or a sequence with at least 95% sequence identity to the sequence of SEQ ID NO:174, a transmembrane domain, and an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain and a costimulatory signaling region comprising an intracellular signaling domain of a T cell costimulatory molecule.
CAR+ T-cell dose range
Administering to the subject a dose of engineered T cells comprising between at or about 1×10^7 CAR+ T cells and at or about 2×10^9 CAR+ T cells, where the CAR comprises an extracellular antigen-binding domain that binds to BCMA, a spacer set forth by SEQ ID NO: 174, a transmembrane domain, and an intracellular signaling region comprising CD3-zeta and a costimulatory signaling region comprising an intracellular signaling domain of 4-1BB.
The claims collectively cover treatment of relapsed or refractory multiple myeloma by administering engineered T cells expressing a BCMA-binding CAR having specified VH/VL CDR sequences, SEQ ID NO: 174 spacer constraints, a transmembrane domain, and CD3-zeta plus costimulatory signaling. The claims further require prior lymphodepleting therapy and prior-therapy refractory or relapsed status, and one claim adds a CAR+ T-cell dose range and 4-1BB costimulatory signaling.
Stated Advantages
The lymphodepleting therapy is framed in terms of engraftment and activity and homeostatic proliferation.
The lymphodepleting therapy is further associated with reduction of CD4+CD25+ regulatory T cells.
The document discusses potential effects on tumor burden and CRS risk.
The document describes homing and activity through SDF-1 and CXCR-4.
Optimized polynucleotides are described as improving RNA homogeneity/expression.
High transcribed RNA homogeneity and minimal RNA heterogeneity.
Improved cell health.
Enrichment for central memory and memory T-cell phenotypes, including central memory CAR+ CD4 and CAR+ CD8 subsets.
Polyfunctional and robust cytokine-producing cells.
Documented Applications
Treating a subject having or suspected of having relapsed or refractory multiple myeloma (R/R MM) using engineered T cells comprising a BCMA-binding CAR, with prior lymphodepleting therapy and specified prior-therapy refractory/relapsed eligibility.
Supporting combination/adjuvant therapies including cytotoxic agents, hypomethylating agents, oncolytic viruses, and immune checkpoint inhibitors or inhibitory nucleic acids targeting immune checkpoints.
Tracking engineered cells using truncated EGFR (tEGFR), PSMA, and CD34/NGFR.
Treatment of a subject having or suspected of having relapsed or refractory multiple myeloma (R/R MM) using BCMA-targeted CAR-engineered T cells.
Use in pharmaceutical compositions and administration concepts, including lyophilized formulations and parenteral administration.
Assessment of response and toxicity endpoints in the context of CRS (cytokine release syndrome) and neurotoxicity.
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