Effector cells and use thereof for allogeneic adoptive cell therapies in solid tumors

Patent metadata

Field	Value
Publication number	US-2025032547-A1
Application number	US-202418917836-A
Country	US
Kind code	A1
Filing date	Oct 16, 2024
Priority date	Oct 20, 2021
Publication date	Jan 30, 2025
Grant date	—

Abstract

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. In various embodiments, the derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

First claim

1 . A cell or a population thereof, wherein:
(i) the cell is (a) an immune cell; (b) an induced pluripotent cell (iPSC), a clonal iPSC, or an iPS cell line cell; or (c) a derivative cell obtained from differentiating the iPSC; (ii) the cell comprises an exogenous polynucleotide encoding a signaling redirector receptor (SRR) that comprises a partial or full peptide of an extracellular domain (ECD) of a signaling receptor and a partial or full peptide of an intracellular domain (ICD) of a cytokine receptor, wherein the signaling receptor and the cytokine receptor are different molecules; (iii) the cell has improved resistance to cytokine immunosuppression in an adoptive cell therapy for solid tumors; and (iv) the cell optionally further comprises one or more of:
an exogenous polynucleotide encoding a CAR (chimeric antigen receptor)
an exogenous polynucleotide encoding a CD16 or a variant thereof,
CD38 knockout; and
an exogenous polynucleotide encoding a cytokine signaling complex comprising a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof.

2 . The cell or population thereof of claim 1 , wherein the signaling redirector receptor comprises:
(a) a partial or full peptide of the extracellular domain (ECD) of a signaling receptor comprising transforming growth factor beta receptor (TGFβR), programmed cell death 1 (PD1), CTLA4, IL10R, IL4R, or any combination thereof, and (b) a partial or full peptide of the intracellular domain (ICD) of a cytokine receptor comprising IL2Rβ, IL12Rβ, IL18Rβ, IL21R, or any combination thereof.

3 . The cell or population thereof of claim 2 , wherein the signaling receptor comprises TGFβR2, wherein the signaling redirector receptor is a TGFβ-SRR, and
(a) wherein the cytokine receptor is IL2Rβ, thereby forming a TGFβR2-IL2Rβ signaling redirector receptor; or
(b) wherein the cytokine receptor is IL12Rβ, thereby forming a TGFβR2-IL12Rβ signaling redirector receptor; or
(c) wherein the cytokine receptor is IL18Rβ, thereby forming a TGFβR2-IL18Rβ signaling redirector receptor; or
(d) wherein the cytokine receptor is IL21R, thereby forming a TGFβR2-IL21R signaling redirector receptor.

4 . The cell or population thereof of claim 3 , wherein:
(a) the intracellular domain (ICD) of IL2Rβ comprises an amino acid sequence represented by SEQ ID NO: 2; or (b) the intracellular domain (ICD) of IL12Rβ comprises an amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 4; or (c) the intracellular domain (ICD) of IL18Rβ comprises an amino acid sequence represented by SEQ ID NO: 5; or (d) the intracellular domain (ICD) of IL21Rβ comprises an amino acid sequence represented by SEQ ID NO: 6; or (e) the extracellular domain (ECD) of TGFβR comprises an amino acid sequence represented by SEQ ID NO: 1.

5 . The cell or population thereof of claim 3 , wherein the TGFβR2-IL12Rβ signaling redirector receptor comprises an amino acid sequence having a sequence identity of at least 80%, 85%, 90%, 95%, or 97%, 98%, or 99% to a sequence represented by SEQ ID NO: 7, wherein an amino acid sequence represented by SEQ ID NO: 8 comprised in SEQ ID NO: 7 is variable.

6 . The cell or population thereof of claim 1 , wherein the cell further comprises:
(i) HLA-I deficiency and/or HLA-II deficiency; (ii) introduction of HLA-G or non-cleavable HLA-G; (iii) deletion or disruption of at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD25, CD69, CD44, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT; or (iv) introduction of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD16, CD47, CD64, CD113, CD131, CD137, CD80, PDL1, A 2A R, TCR, chimeric fusion receptor (CFR), Fc receptor, an antibody or functional variant or fragment thereof, a checkpoint inhibitor, an engager, and surface triggering receptor for coupling with bi- or multi-specific or universal engagers.

7 . The cell or population thereof of claim 1 , wherein the cell comprises HLA-I deficiency and/or HLA-II deficiency; and optionally,
wherein the cell comprises an exogenous polynucleotide encoding HLA-G, HLA-E, or a variant thereof.

8 . The cell or population thereof of claim 7 , wherein the HLA-I deficiency comprises deletion or disruption of at least one of: B2M, TAP1, TAP2, and Tapasin; or
wherein the HLA-II deficiency comprises deletion or disruption of at least one of: CIITA, RFX5, RFXAP, and RFXANK.

9 . The cell or population thereof of claim 1 , wherein the derivative cell:
(a) comprises a derivative CD34 + cell, a derivative hematopoietic stem and progenitor cell, a derivative hematopoietic multipotent progenitor cell, a derivative T cell progenitor, a derivative NK cell progenitor, a derivative T cell, a derivative NKT cell, a derivative NK cell, a derivative B cell, or a derivative effector cell having one or more functional features that are not present in a counterpart primary T, NK, NKT, and/or B cell; (b) is an allogeneic effector cell, wherein the effector cell is a derivative NK cell or a derivative T cell having at least one of the following characteristics comprising:
(i) improved persistency and/or survival;
(ii) increased resistance to activated recipient immune cells;
(iii) increased cytotoxicity;
(iv) improved tumor penetration;
(v) enhanced or acquired ADCC;
(vi) enhanced ability in migrating, and/or activating or recruiting bystander immune cells, to tumor sites;
(vii) enhanced ability to reduce tumor immunosuppression;
(viii) improved ability in rescuing tumor antigen escape; and
(ix) reduced fratricide,
in comparison to its native counterpart cell obtained from peripheral blood, umbilical cord blood, or other donor tissues.

10 . The cell or population thereof of claim 1 , wherein the exogenous CD16 comprises at least one of:
(a) a high affinity non-cleavable CD16 (hnCD16) or a variant thereof; (b) F176V and S197P in ectodomain domain of CD16; (c) a full or partial ectodomain originated from CD64; (d) a non-native (or non-CD16) transmembrane domain; (e) a non-native (or non-CD16) intracellular domain; (f) a non-native (or non-CD16) signaling domain; (g) a non-native stimulatory domain; and (h) transmembrane, signaling, and stimulatory domains that are not originated from CD16, and are originated from a same or different polypeptide.

11 . The cell or population thereof of claim 10 , wherein:
(a) the non-native transmembrane domain is derived from a CD3δ, CD3ε, CD3γ, CD3ζ, CD4, CD8, CD8a, CD8b, CD27, CD28, CD40, CD84, CD166, 4-1BB, OX40, ICOS, ICAM-1, CTLA-4, PD-1, LAG-3, 2B4, BTLA, CD16, IL7, IL12, IL15, KIR2DL4, KIR2DS1, NKp30, NKp44, NKp46, NKG2C, NKG2D, or T cell receptor (TCR) polypeptide; (b) the non-native stimulatory domain is derived from a CD27, CD28, 4-1BB, OX40, ICOS, PD-1, LAG-3, 2B4, BTLA, DAP10, DAP12, CTLA-4, or NKG2D polypeptide; (c) the non-native signaling domain is derived from a CD30, 2B4, DAP10, DAP12, DNAM1, CD137 (4-1BB), IL21, IL7, IL12, IL15, NKp30, NKp44, NKp46, NKG2C, or NKG2D polypeptide; or (d) the non-native transmembrane domain is derived from NKG2D, the non-native stimulatory domain is derived from 2B4, and the non-native signaling domain is derived from CD3ζ.

12 . The cell or population thereof of claim 1 , wherein the CAR is:
(i) T cell specific or NK cell specific; (ii) a bi-specific antigen binding CAR; (iii) a switchable CAR; (iv) a dimerized CAR; (v) a split CAR; (vi) a multi-chain CAR; (vii) an inducible CAR; (viii) co-expressed with a cytokine signaling complex comprising a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof, opt

Assignees

• Fate Therapeutics Inc

Inventors

• Carron Emily
• Peralta Eigen
• Valamehr Bahram
• Chu Hui-Yi
• Lee Tom Tong

Classifications

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• C12N5/0696

  Artificially induced pluripotent stem cells, e.g. iPS · CPC title

• A61K2239/58

  Prostate · CPC title

• A61K2239/59

  Reproductive system, e.g. uterus, ovaries, cervix or testes · CPC title

• A61K2239/49

  Breast · CPC title