Modified stem cell memory T cells, methods of making and methods of using same
Inventors
Ostertag, Eric • Shedlock, Devon
Assignees
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Publication Number
US-10513686-B2
Publication Date
2019-12-24
Expiration Date
Abstract
The disclosure provides a method of producing modified stem memory T cells (e.g. CAR-T cells) for administration to a subject as, for example an adoptive cell therapy.
Core Innovation
The invention provides a composition comprising a population of modified T-cells in which a plurality of the modified T-cells comprise a non-naturally occurring antigen receptor or a sequence encoding the same. The composition is characterized by enrichment for stem memory T cell (T_SCM) or T_SCM-like phenotypes, where at least 25% of the modified T-cells express one or more cell-surface marker(s) of a stem memory T cell or a T_SCM-like cell, including CD45RA and CD62L.
The antigen receptor is not naturally occurring and includes chimeric antigen receptor (CAR) implementations. Additional constraints further refine the stem memory or T_SCM-like marker expression by including additional cell-surface markers and higher minimum percentage thresholds, including CD28, CCR7, CD127, CD45RO, CD95, and IL-2Rβ.
The related description further characterizes how antigen receptor sequences and therapeutic components are introduced into primary human T cells, including adoptive CAR-T/TCR-T approaches using transposon/transposase systems and related genomic editing constructs. It describes piggyBac and Super piggyBac, Sleeping Beauty, Helraiser/Helitron features, Tol2, cis-regulatory insulator elements, homologous recombination, CRISPR-associated protein Cas9 options, TALEN, ZFN, type IIS endonucleases, and alternative delivery vectors including viral vectors, DNA/RNA vectors, and nanoparticles.
Claims Coverage
The consolidated independent claim coverage centers on a modified T-cell composition with a non-naturally occurring antigen receptor and T_SCM/T_SCM-like enrichment defined by CD45RA and CD62L in at least 25% of the population.
Modified T-cell composition with non-naturally occurring antigen receptor
A composition comprising a population of modified T-cells wherein a plurality of the modified T-cells comprise a non-naturally occurring antigen receptor or a sequence encoding the same.
T_SCM/T_SCM-like marker enrichment with CD45RA and CD62L
At least 25% of the population of modified T-cells expresses one or more cell-surface marker(s) of a stem memory T cell (T_SCM) or a T_SCM-like cell, wherein the one or more cell-surface marker(s) comprise CD45RA and CD62L.
CAR-specific antigen receptor implementation
The non-naturally occurring antigen receptor is a chimeric antigen receptor (CAR).
Higher stem memory marker threshold
At least 30% of the modified T cells express CD62L and CD45RA.
Additional stem/memory-associated marker set with defined threshold
At least 25% of modified T cells in the population express CD127, CD45RO, CD95, and/or IL-2Rβ.
Genomic editing composition defined by DNA binding and nuclease domains
A genomic editing composition includes a DNA binding domain sequence and a nuclease domain sequence.
Transposase composition using piggyBac or piggyBac-like systems
A transposase composition includes a piggyBac transposase or a sequence encoding a piggyBac or piggyBac-like transposase.
The consolidated claim coverage is directed to modified T-cell compositions carrying a non-naturally occurring antigen receptor and enriched for T_SCM/T_SCM-like phenotypes defined by CD45RA and CD62L, with dependent refinements including CAR, higher marker thresholds, additional marker sets, genomic editing domain architectures, and piggyBac-based transposase systems.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic use for clotting and other diseases, including Hemophilia B (Factor IX) and other coagulation-related conditions supported by coagulation cascade rationale and factor-related protein expression.
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