IP Library › Granted Patent US 12,448,430
Granted Patent B2
US 12,448,430 · App. 17/438,380 · Granted Oct 21, 2025

High avidity WT1 T cell receptors and uses thereof

Inventors: Thomas M. Schmitt (Seattle, WA); Aude G. Chapuis (Seattle, WA); Philip D. Greenberg (Mercer Island, WA)
Assignee: FRED HUTCHINSON CANCER CENTER
C07K14/7051A61K40/11A61K40/32A61K40/4243A61P35/00C12N5/0636A61K38/00A61K2239/49A61K2239/54
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,448,430
App. No.
17/438,380
Granted
Oct 21, 2025
Kind
B2
Abstract

The present disclosure provides T cell receptors (TCRs) and related binding proteins with high functional avidity against tumor associated antigen p37 from Wilms tumor protein 1 (WT1), T cells expressing such high affinity WT1 specific TCRs, nucleic acids encoding the same, and compositions for use in treating diseases or disorders in which cells overexpress WT1 and/or produce the p37 antigen, such as in cancer.

Claims (124)

1. A host cell comprising a heterologous polynucleotide encoding a T cell receptor (TCR), wherein the TCR comprises:

(a) a TCR α-chain variable (Vα) domain comprising the CDR1α amino acid sequence set forth in SEQ ID NO:194, the CDR2a amino acid sequence set forth in SEQ ID NO:195, and the CDR3a amino acid sequence set forth in SEQ ID NO:196 or 12; and

(b) a TCR β-chain variable (VB) domain comprising the CDR1β amino acid sequence set forth in SEQ ID NO:197, the CDR2β amino acid sequence set forth in SEQ ID NO:198, and the CDR3β amino acid sequence set forth in SEQ ID NO:199 or 1,

wherein the TCR binds to a VLDFAPPGA (SEQ ID NO:59): human leukocyte antigen (HLA) complex, wherein the HLA comprises HLA-A*201.

2. The host cell of claim 1 , wherein the TCR specifically binds to the VLDFAPPGA (SEQ ID NO:59): HLA complex.

3. The host cell of claim 1 , wherein the TCR further binds to the VLDFAPPGA (SEQ ID NO:59): human leukocyte antigen (HLA) complex on a cell surface independent of CD8 or in the absence of CD8.

4. The host cell of claim 1 , wherein:

(a) the Vα domain of the TCR comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:253; and/or;

(b) the Vβ domain of the TCR comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:242.

5. The host cell of claim 1 , wherein the Vα domain of the TCR comprises the amino acid sequence set forth in SEQ ID NO:253, and/or wherein the Vβ domain of the TCR comprises the amino acid sequence set forth in SEQ ID NO:242.

6. The host cell of claim 1 , wherein:

(i) the Vα domain of the TCR consists of the amino acid sequence set forth in SEQ ID NO:253; and/or

(ii) the VB domain of the TCR consists of the amino acid sequence set forth in SEQ ID NO:242.

7. The host cell of claim 1 , wherein the TCR further comprises:

(i) a TCR α-chain constant domain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:47; and/or

(ii) a TCR β-chain constant domain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:45 or 46.

8. The host cell of claim 7 , wherein the TCR α-chain constant domain and the TCR β-chain constant domain comprise a non-native cysteine.

9. The host cell of claim 1 , wherein the TCR comprises a TCR α-chain comprising the Vα domain and an α-chain constant domain, wherein

the Vα domain comprises the amino acid sequence set forth in SEQ ID NO: 253, and the α-chain constant domain comprises the amino acid sequence of SEQ ID NO:47.

10. The host cell of claim 1 , wherein the TCR comprises a TCR β-chain comprising the Vβ domain and a β-chain constant domain, wherein the Vβ domain comprises the amino acid sequence set forth in SEQ ID NO:242, and the β-chain constant domain comprises the amino acid sequence of SEQ ID NO:45 or 46.

11. The host cell of claim 1 , wherein the TCR comprises a TCR β-chain comprising the Vβ domain and a β-chain constant domain, wherein:

the Vβ domain consists of the amino acid sequence set forth in SEQ ID NO:242, and the β-chain constant domain consists of the amino acid sequence of SEQ ID NO:45 or 46.

12. The host cell of claim 1 , wherein:

the Vα domain and the Vβ domain of the TCR comprise the amino acid sequences set forth in SEQ ID NOs:253 and 242, respectively.

13. The host cell of claim 12 , wherein the TCR further comprises an α-chain constant domain and/or a β-chain constant domain, wherein the α-chain constant domain comprises the amino acid sequence set forth in SEQ ID NO:47, and wherein the β-chain constant domain comprises the amino acid sequence set forth SEQ ID NO:46.

14. The host cell of claim 1 , wherein the TCR comprises a single-chain TCR (scTCR) or a CAR.

15. The host cell of claim 1 , wherein the heterologous polynucleotide encoding the TCR:

(i) is codon optimized for the host cell;

(ii) has at least 75% identity to or comprises the nucleotide sequence set forth in any one of SEQ ID NOs:64, 75, 86, 97, 108, 109, 110, 111, 122, 133, and 144;

(iii) has at least 95% identity to or comprises the polynucleotide sequence set forth in SEQ ID NO:155; or

(iv) encodes an amino acid sequence having at least 95% identity to or comprising the amino acid sequence set forth in SEQ ID NO:48.

16. The host cell of claim 1 , wherein the heterologous polynucleotide encoding the TCR further comprises:

(i) a polynucleotide encoding a polypeptide that comprises an extracellular portion of a CD8 co-receptor α chain;

ii a polynucleotide encoding a polypeptide that comprises an extracellular portion of a CD8 co-receptor β chain; and/or

(iii) the polynucleotide of (i) and the polynucleotide of (ii); and/or

(iv) the polynucleotide of (i) and the polynucleotide of (ii), and further comprises a polynucleotide encoding a self-cleaving peptide disposed between the polynucleotide of (i) and the polynucleotide of (ii); and/or

(v) the polynucleotide of (i) and the polynucleotide of (ii), and further comprises a polynucleotide encoding a self-cleaving peptide disposed between the polynucleotide encoding the TCR and the polynucleotide of (i) and/or between the polynucleotide encoding the TCR and the polynucleotide of (ii); and/or

(vi) a polynucleotide encoding a self-cleaving peptide disposed between a polynucleotide encoding a TCRα chain of the TCR and a polynucleotide encoding a TCRβ chain of the TCR.

17. The host cell of claim 16 , wherein the heterologous polynucleotide comprises, operably linked in-frame:

(i) (pnCD8α)-(pnSCP 1 )-(pnCD8β)-(pnSCP 2 )-(pnTCR);

(ii) (pnCD8β)-(pnSCP 1 )-(pnCD8α)-(pnSCP 2 )-(pnTCR);

iii) (pnTCR)-(pnSCP 1 )-(pnCD8α)-(pnSCP 2 )-(pnCD8β);

(iv) (pnTCR)-(pnSCP 1 )-(pnCD8β)-(pnSCP 2 )-(pnCD8α);

(v) (pnCD8α)-(pnSCP 1 )-(pnTCR)-(pnSCP 2 )-(pnCD8β); or

(vi) (pnCD8β)-(pnSCP 1 )-(pnTCR)-(pnSCP 2 )-(pnCD8α),

wherein pnCD8a is the polynucleotide encoding the polypeptide that comprises the extracellular portion of the CD8 co-receptor a chain,

wherein pnCD8β is the polynucleotide encoding the polypeptide that comprises the extracellular portion of the CD8 co-receptor chain,

wherein pnTCR is the polynucleotide encoding the TCR,

and wherein pnSCP 1 and pnSCP 2 are each independently a polynucleotide encoding a self-cleaving peptide, wherein the polynucleotides and/or the encoded self-cleaving peptides are the same or different.

18. The host cell of claim 17 , wherein the heterologous polynucleotide comprises, operably linked in-frame:

(i) (pnCD8α)-(pnSCP 1 )-(pnCD8β)-(pnSCP 2 )-(pnTCRβ)-(pnSCP 3 )-(pnTCRα);

(ii) (pnCD8β)-(pnSCP 1 )-(pnCD8α)-(pnSCP 2 )-(pnTCRβ)-(pnSCP 3 )-(pnTCRα);

(iii) (pnCD8α)-(pnSCP 1 )-(pnCD8β)-(pnSCP 2 )-(pnTCRα)-(pnSCP 3 )-(pnTCRβ);

(iv) (pnCD8β)-(pnSCP 1 )-(pnCD8α)-(pnSCP 2 )-(pnTCRα)-(pnSCP 3 )-(pnTCRβ);

(v) (pnTCRβ)-(pnSCP 1 )-(pnTCRα)-(pnSCP 2 )-(pnCD8α)-(pnSCP 3 )-(pnCD8β);

(vi) (pnTCRβ)-(pnSCP 1 )-(pnTCRα)-(pnSCP 2 )-(pnCD8β)-(pnSCP 3 )-(pnCD8α);

(vii) (pnTCRα)-(pnSCP 1 )-(pnTCRβ)-(pnSCP 2 )-(pnCD8α)-(pnSCP 3 )-(pnCD8β); or

(viii) (pnTCRα)-(pnSCP 1 )-(pnTCRβ)-(pnSCP 2 )-(pnCD8β)-(pnSCP 3 )-(pnCD8α),

wherein pnCD8α is the polynucleotide encoding the polypeptide that comprises the extracellular portion of the CD8 co-receptor a chain,

wherein pnCD8β is the polynucleotide encoding the polypeptide that comprises the extracellular portion of the CD8 co-receptor chain,

wherein pnTCRα is the polynucleotide encoding the TCR α chain,

wherein pnTCRβ is the polynucleotide encoding the TCR β chain,

and wherein pnSCP 1 , pnSCP 2 , and pnSCP 3 are each independently a polynucleotide encoding a self-cleaving peptide, wherein the polynucleotides and/or the encoded self-cleaving peptides are the same or different.

19. The host cell of claim 18 , wherein the encoded TCR α-chain, self-cleaving peptide, and TCR β-chain comprise an amino acid sequence having at least 95% identity to SEQ ID NO:48.

20. The host cell of claim 1 , wherein the host cell is a hematopoietic progenitor cell or a human immune system cell.

21. The host cell of claim 20 , wherein:

(i) the immune system cell is a CD4+T cell, a CD8+T cell, a CD4-CD8-double negative T cell, a y& T cell, a natural killer cell, a natural killer T cell, dendritic cell, or any combination thereof, wherein, optionally, the combination, if present, comprises a CD4+T cell and a CD8+T cell; or

(ii) the immune system cell is a T cell, wherein the T cell is a naïve T cell, a central memory T cell, an effector memory T cell, or any combination thereof.

22. A method for alleviating symptoms or prolonging survival of a human subject having a hyperproliferative or proliferative disorder characterized by WT1 overexpression, comprising administering to the human subject an effective amount of the host cell of claim 20 .

23. The method of claim 22 , wherein the TCR is expressed on the surface of the host cell and wherein the host cell is a hematopoietic progenitor cell or a human immune system cell selected from a CD4+T cell, a CD8+T cell, a CD4-CD8-double negative T cell, a γδ T cell, a natural killer cell, a natural killer T cell, a dendritic cell, or any combination thereof.

24. The method of claim 23 , wherein the host cell is a CD4+cell, a CD8+T cell, or both.

25. The method of claim 24 , wherein the host cell is a CD8+T cell.

26. The method of claim 22 , wherein the hyperproliferative or proliferative disorder is a hematological malignancy or a solid cancer.

27. The method of claim 26 , wherein:

(i) the hematological malignancy is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia (CEL), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or multiple myeloma (MM); and/or

(ii) the solid cancer is selected from breast cancer, ovarian cancer, lung cancer, biliary cancer, bladder cancer, bone and soft tissue carcinoma, brain tumor, cervical cancer, colon cancer, colorectal adenocarcinoma, colorectal cancer, desmoid tumor, embryonal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastric adenocarcinoma, glioblastoma multiforme, gynecological tumor, head and neck squamous cell carcinoma, hepatic cancer, mesothelioma, malignant melanoma, osteosarcoma, pancreatic cancer, pancreatic ductal adenocarcinoma, primary astrocytic tumor, primary thyroid cancer, prostate cancer, renal cancer, renal cell carcinoma, rhabdomyosarcoma, skin cancer, soft tissue sarcoma, testicular germ-cell tumor, urothelial cancer, uterine sarcoma, or uterine cancer.

28. An adoptive immunotherapy method for alleviating symptoms or prolonging survival of a subject having a hyperproliferative or proliferative disorder characterized by WT1 overexpression, comprising administering to the subject an effective amount of the host cell of claim 20 , wherein:

(a) the subject is human; and/or

(b) the host cell was modified ex vivo to comprise the heterologous polynucleotide encoding the TCR, wherein, optionally, the recombinant host cell is an allogeneic cell, a syngeneic cell, or an autologous cell to the subject; and/or

(c) the host cell is formulated for parenteral administration, wherein, optionally, the host cell is formulated for administration to the subject at a dose of about 10 7 cells/m 2 to about 10 11 cells/m 2 ; and/or

(d) the host cell is formulated for administering a plurality of doses of the host cell to the subject, wherein, optionally, the plurality of doses are formulated for administration at intervals between administrations of about two to about four weeks; and/or

(e) the subject is further receiving immunosuppressive therapy, wherein, optionally, the immunosuppressive therapy is selected from calcineurin inhibitors, corticosteroids, microtubule inhibitors, low dose of a mycophenolic acid prodrug, or any combination thereof; and/or

(f) the subject has received a non-myeloablative or a myeloablative hematopoietic cell transplant; wherein, optionally, the subject is administered the host cell at least three months after the non-myeloablative hematopoietic cell transplant; wherein, further optionally, the subject is administered the host cell at least two months after the myeloablative hematopoietic cell transplant; and/or

(g) the subject has received or is receiving an immune checkpoint inhibitor and/or an agonist of a stimulatory immune checkpoint agent.

29. The host cell of claim 1 , wherein the host cell is a T cell.

30. The host cell of claim 1 , wherein the host cell is capable of killing:

(i) a tumor cell of breast cancer cell line MDA-MB-468;

(ii) a tumor cell of pancreatic adenocarcinoma cell line PANC-1;

(iii) a tumor cell of breast cancer cell line MDA-MB-231;

(iv) a tumor cell of myelogenous leukemia cell line K562 expressing an HLA-A2, wherein, optionally, the HLA-A2 comprises HLA-A*201;

(v) a tumor cell of colon carcinoma cell line RKO expressing an HLA-A2, wherein, optionally, the HLA-A2 comprises HLA-A*201; or

(vi) any combination of tumor cells of (i)-(v),

when the host cell and the tumor cell are both present in a sample.

31. A composition, comprising the host cell of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

32. The composition of claim 31 , wherein the composition comprises a host CD4+T cell and/or a host CD8+T cell.

33. A unit dose form comprising the host cell of claim 1 , wherein the host cell is at a dose of about 10 7 cells/m 2 to about 10 11 cells/m 2 .

34. The host cell of claim 1 , wherein:

(i) the Vα domain of the TCR consists of the amino acid sequence set forth in SEQ ID NO.: 253; and

(ii) the Vβ domain of the TCR consists of the amino acid sequence set forth in SEQ ID NO.: 242.

35. The host cell of claim 1 , wherein the TCR comprises a TCR α-chain comprising the Vα domain and an α-chain constant domain, wherein the Vα domain consists of the amino acid sequence set forth in SEQ ID NO:253, and the α-chain constant domain consists of the amino acid sequence of SEQ ID NO:47.

36. The host cell of claim 1 , wherein the Vα domain and the Vβ domain of the TCR consist of the amino acid sequences set forth in SEQ ID NOs:253 and 242, respectively, and wherein the TCR comprises a TCR α-chain constant domain and a TCR β-chain constant domain, and wherein the TCR α-chain constant domain and the TCR β-chain constant domain comprise a non-native cysteine.

37. The host cell of claim 1 , wherein the polynucleotide encoding the TCR comprises (a) a sequence encoding the amino acid sequence set forth in SEQ ID NO:34, and/or (b) a sequence encoding the amino acid sequence set forth in SEQ ID NO:23.

38. The host cell of claim 1 , wherein the polynucleotide encoding the TCR comprises (a) a sequence encoding an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO.: 34, and (b) a sequence encoding an amino acid sequence having at least 98% sequence identity to the amino acid sequence of SEQ ID NO:47.

39. The host cell of claim 1 , wherein the polynucleotide encoding the TCR comprises (a) a sequence encoding an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO.: 23, and (b) a sequence encoding the amino acid sequence of SEQ ID NO:45 or a sequence encoding an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:46.

40. The host cell of claim 1 , wherein the polynucleotide encoding the TCR comprises a sequence encoding the amino acid sequence set forth in SEQ ID NO.: 23, and a sequence encoding the amino acid sequence of SEQ ID NO:46.

41. The host cell of claim 1 , wherein the TCR comprises a TCR a chain and a TCR β-chain.

42. A recombinant expression vector comprising a heterologous polynucleotide encoding a T cell receptor (TCR) operably linked to an expression control sequence, wherein the TCR comprises:

(a) a TCR α-chain variable (Vα) domain comprising the CDR1α amino acid sequence set forth in SEQ ID NO:194, the CDR2a amino acid sequence set forth in SEQ ID NO:195, and the CDR3a amino acid sequence set forth in SEQ ID NO:196 or 12; and

(b) a TCR β-chain variable (VB) domain comprising the CDR1β amino acid sequence set forth in SEQ ID NO:197, the CDR2β amino acid sequence set forth in SEQ ID NO:198, and the CDR3β amino acid sequence set forth in SEQ ID NO:199 or 1,

wherein the TCR binds to a VLDFAPPGA (SEQ ID NO:59): human leukocyte antigen (HLA) complex, wherein the HLA comprises HLA-A*201.

43. The recombinant expression vector of claim 42 , wherein:

(i) the Vα domain comprises the amino acid sequence set forth in SEQ ID NO: 253 and/or

(ii) the Vβ domain comprises the amino acid sequence set forth in SEQ ID NO: 242.

44. The recombinant expression vector of claim 42 , wherein the TCR comprises a TCR α-chain constant domain and a TCR β-chain constant domain, and wherein the TCR α-chain constant domain and the TCR β-chain constant domain comprise a non-native cysteine.

45. The recombinant expression vector of claim 44 , wherein the α-chain constant domain comprises the amino acid sequence set forth in SEQ ID NO:47, and wherein the β chain constant domain comprises the amino acid sequence set forth SEQ ID NO:46.

46. The recombinant expression vector of claim 42 , wherein the vector is a viral vector selected from an adenoviral vector, a lentiviral vector, or a y-retroviral vector.

47. The recombinant expression vector of claim 42 , wherein the polynucleotide encoding the TCR comprises:

(i) a sequence encoding the amino acid sequence set forth in SEQ ID NO:34 and/or

(ii) a sequence encoding the amino acid sequence set forth in SEQ ID NO:23.

48. A T cell receptor (TCR) comprising a TCR α-chain and a TCR β-chain, wherein:

(i) the TCR α-chain comprises the CDR1a amino acid sequence set forth in SEQ ID NO:194, the CDR2a amino acid sequence set forth in SEQ ID NO:195, and the CDR3a amino acid sequence set forth in SEQ ID NO:196 or 12;

(ii) the TCR β-chain comprises the CDR1β amino acid sequence set forth in SEQ ID NO:197, the CDR2β amino acid sequence set forth in SEQ ID NO:198, and the CDR3β amino acid sequence set forth in SEQ ID NO:199 or 1; and

(iii) the TCR α-chain, the TCR β-chain, or both, comprise a non-native cysteine in a respective TCR constant domain.

49. The TCR of claim 48 , wherein the TCR α-chain comprises the amino acid sequence set forth in SEQ ID NO:47, and wherein the TCR β-chain comprises the amino acid sequence set forth SEQ ID NO:46.

Assignments (3)
MERGER AND CHANGE OF NAME Recorded Sep 3, 2025
From: FRED HUTCHINSON CANCER RESEARCH CENTER; SEATTLE CANCER CARE ALLIANCE
To: FRED HUTCHINSON CANCER CENTER
Reel/Frame 072793/0308 →
CONFIRMATORY LICENSE Recorded Dec 12, 2023
From: FRED HUTCHINSON CANCER RESEARCH CENTER
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065967/0493 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: SCHMITT, THOMAS M.; CHAPUIS, AUDE G.; GREENBERG, PHILIP D.
To: FRED HUTCHINSON CANCER RESEARCH CENTER
Reel/Frame 060358/0656 →
Continuity (2)
Provisional Application 62816746 · Mar 11, 2019
Related Publication 20220160764A1 · May 26, 2022
References Cited (170)
US 5283173A · Fields et al. · 1994 [cited by applicant]
US 5420032A · Marshall et al. · 1995 [cited by applicant]
US 5468614A · Fields et al. · 1995 [cited by applicant]
US 6833252B1 · Dujon et al. · 2004 [cited by applicant]
US 7342092B2 · Sugiyama · 2008 [cited by applicant]
US 7608685B1 · Sugiyama et al. · 2009 [cited by applicant]
US 7622119B2 · Sugiyama · 2009 [cited by applicant]
US 8119772B2 · Yang et al. · 2012 [cited by applicant]
US 8697359B1 · Zhang · 2014 [cited by applicant]
US 9574000B2 · Langermann et al. · 2017 [cited by applicant]
US 20040002092A1 · Arnould et al. · 2004 [cited by applicant]
US 20040087025A1 · June et al. · 2004 [cited by applicant]
US 20060078552A1 · Arnould et al. · 2006 [cited by applicant]
US 20060153826A1 · Arnould et al. · 2006 [cited by applicant]
US 20060206949A1 · Arnould et al. · 2006 [cited by applicant]
US 20070117128A1 · Smith et al. · 2007 [cited by applicant]
US 20110189141A1 · Kieback et al. · 2011 [cited by applicant]
US 20110243972A1 · Jaffee · 2011 [cited by applicant]
US 20110301073A1 · Gregory et al. · 2011 [cited by applicant]
US 20140068797A1 · Doudna et al. · 2014 [cited by applicant]
US 20140186843A1 · Zhang et al. · 2014 [cited by applicant]
US 20170088895A1 · Han · 2017 [cited by examiner]
US 20190085081A1 · Bicknell et al. · 2019 [cited by applicant]
JP WO2017501130A · 2017 [cited by applicant]
WO WO9709433A1 · 1997 [cited by applicant]
WO WO2005056595A2 · 2005 [cited by applicant]
WO WO2010084158A1 · 2010 [cited by applicant]
WO WO2013025779A1 · 2013 [cited by applicant]
WO WO2015071474A2 · 2015 [cited by applicant]
WO WO2015077615A1 · 2015 [cited by applicant]
WO WO2016022400A1 · 2016 [cited by applicant]
WO WO2016040724A1 · 2016 [cited by applicant]
WO WO2016054638A1 · 2016 [cited by applicant]
WO WO2016134333A1 · 2016 [cited by applicant]
WO WO2016141357A1 · 2016 [cited by applicant]
WO WO2017021526A1 · 2017 [cited by applicant]
WO WO2017059084A1 · 2017 [cited by applicant]
WO WO2017112944A1 · 2017 [cited by applicant]
WO WO2018058002A1 · 2018 [cited by applicant]
WO WO2018197492A1 · 2018 [cited by applicant]
WO WO2019178427A1 · 2019 [cited by applicant]
Milighetti et al. Intra- and inter-chain contacts determine TCR specificity: applying protein co-evolution methods to TCRab pairing. bioRxiv doi: https://doi.org/10.1101/2024.05.24.595718; posted May 29, 2024. p. 1-51 (… [cited by examiner]
Seladi-Schulman. Curing Cancer: Newer Treatments to Keep an Eye On. Downloaded from https://www.healthline.com/health/is-there-a-cure-for-cancer#overview. Published online May 19, 2023. p. 1-10. (Year: 2023). [cited by examiner]
Altschul et al., “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,” [cited by applicant]
Argast et al., “I-PpoI and I-CreI Homing Site Sequence Degeneracy Determined by Random Mutagenesis and Sequential in Vitro Enrichment,” [cited by applicant]
Ashworth et al., “Computational redesign of endonuclease DNA binding and cleavage specificity,” [cited by applicant]
Belfort et al., “Homing endonucleases: keeping the house in order,” [cited by applicant]
Betts et al., “The Functional Profile of Primary Human Antiviral CD8+ T Cell Effector Activity Is Dictated by Cognate Peptide Concentration,” [cited by applicant]
Cavallo et al., “2011: the immune hallmarks of cancer,” [cited by applicant]
Cawthon et al., “Peptide Requirement for CTL Activation Reflects the Sensitivity to CD3 Engagement: Correlation with CD8αβ Versus CD8aa Expression,” [cited by applicant]
Chapuis et al., “Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype,” [cited by applicant]
Chapuis et al., “Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients,” [cited by applicant]
Cheever et al., “The Prioritization of Cancer Antigens: A National Cancer Institute Pilot Project for the Acceleration of Translational Research,” [cited by applicant]
Chen et al., “Oncology Meets Immunology: The Cancer-Immunity Cycle,” [cited by applicant]
Chevalier et al., “Design, Activity, and Structure of a Highly Specific Artificial Endonuclease,” [cited by applicant]
Chothia et al., “The outline structure of the T-cell αβ receptor,” [cited by applicant]
Cole et al., “CD8: Adhesion Molecule, Co-Receptor and Immuno-Modulator,” [cited by applicant]
Coosemans et al., “Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies,” [cited by applicant]
Dangaj et al., “Novel Recombinant Human B7-H4 Antibodies Overcome Tumoral Immune Escape to Potentiate T-Cell Antitumor Responses,” [cited by applicant]
Desjarlais et al., “Use of a zinc-finger consensus sequence framework and specificity rules to design specific DNA binding proteins,” [cited by applicant]
Di Stasi et al., “Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy,” [cited by applicant]
Dossett et al., “Adoptive Immunotherapy of Disseminated Leukemia With TCR-transduced, CD8 [cited by applicant]
Dudley et al., “Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens,” [cited by applicant]
Dujon et al., “Mobile introns: definition of terms and recommended nomenclature,” [cited by applicant]
Epinat et al., “A novel engineered meganuclease induces homologous recombination in yeast and mammalian cells,” [cited by applicant]
Fehse et al., “CD34 Splice Variant: An Attractive Marker for Selection of Gene-Modified Cells,” [cited by applicant]
Floros et al., “Anticancer Cytokines: Biology and Clinical Effects of IFN-α2, IL-2, IL-15, IL-21, and IL-12,” [cited by applicant]
Gao et al., “Molecular interactions of coreceptor CD8 and MCH class I: the molecular basis for functional coordination with the T-cell receptor,” [cited by applicant]
Gimble et al., “Substrate Recognition and Induced DNA Distortion by the PI-SceI Endonuclease, an Enzyme Generated by Protein Splicing,” [cited by applicant]
Govers et al., “T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing,” [cited by applicant]
Green et al., “Mitichondria and Apoptosis,” [cited by applicant]
Hanahan et al., “Hallmarks of Cancer: The Next Generation,” [cited by applicant]
Hanahan et al., “The Hallmarks of Cancer,” [cited by applicant]
Harris et al., “Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors,” [cited by applicant]
Heemskerk et al., “Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining … [cited by applicant]
Ho et al., “In vitro methods for generating CD8 [cited by applicant]
Howie et al., “High-throughput pairing of T cell receptor a and B sequences,” [cited by applicant]
Hylander et al., “Expression of Wilms tumor gene (WT1) in epithelial ovarian cancer,” [cited by applicant]
International Search Report and Written Opinion, mailed Sep. 14, 2020, for International Application No. PCT/US2020/021916. (25 pages). [cited by applicant]
Jaigirdar et al., “A high avidity WTI reactive T cell receptor mediates recognition of peptide and processed antigen but not naturally occurring WTI positive tumor cells,” [cited by applicant]
Jasin, “Genetic manipulation of genomes with rare-cutting endonucleases,” [cited by applicant]
Jinek et al., “A programmable dual RNA-guided DNA endonuclease in adaptive bacterial immunity,” [cited by applicant]
Jores et al., “Resolution of hypervariable regions in T-cell receptor β chains by a modified Wu-Kabat index of amino acid diversity,” [cited by applicant]
Kalos et al., “T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia,” [cited by applicant]
Kieback et al., “A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer,” [cited by applicant]
Kochenderfer et al., “Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19,” [cited by applicant]
Kuball et al., “Facilitating matched pairing and expression of TCR chains introduced into human T cells,” [cited by applicant]
Kyrgidis et al., “Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications,” [cited by applicant]
Langenkamp et al., “T cell priming by dendritic cells: thresholds for proliferation, differentiation and death and intraclonal functional diversification,” [cited by applicant]
Leen et al., “Improving T Cell Therapy for Cancer,” [cited by applicant]
Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” [cited by applicant]
Liu et al., “Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity,” [cited by applicant]
Luescher et al., “CD8 modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes,” [cited by applicant]
Mautino et al., “Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy,” Proceedings: AACR 104th Annual Meeting 2013, American Association for Cancer Researc… [cited by applicant]
Mavilio et al., “Peripheral Blood Lymphocytes as Target Cells of Retroviral Vector-Mediated Gene Transfer,” [cited by applicant]
Menssen et al., “Presence of Wilms' tumor gene (wt1) transcripts and the WTI nuclear protein in the majority of human acute leukemias,” [cited by applicant]
Morgan et al., “Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes,” [cited by applicant]
Nakatsuka et al., “Immunohistochemical detection of WT1 protein in a variety of cancer cells,” [cited by applicant]
Oji et al., “Expression of the Wilms' Tumor Gene WTI in Solid Tumors and Its Involvement in Tumor Cell Growth,” [cited by applicant]
Oji et al., “Overexpression of the Wilms' Tumor Gene WTI in De Novo Lung Cancers,” [cited by applicant]
Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews [cited by applicant]
Park et al., “Cancer Stem Cell-Directed Therapies: Recent Data From the Laboratory and Clinic,” [cited by applicant]
Penix et al., “Two Essential Regulatory Elements in the Human Interferon γ Promoter Confer Activation Specific Expression in T Cells,” [cited by applicant]
Perler et al., “Protein splicing elements: inteins and exteins—a definition of terms and recommended nomenclature,” [cited by applicant]
Philip et al., “A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy,” [cited by applicant]
Pittet et al., “α3 Domain Mutants of Peptide/MHC Class I Multimers Allow the Selective Isolation of High Avidity Tumor-Reactive CD8 T Cells,” [cited by applicant]
Porter et al., “Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia,” [cited by applicant]
Porteus et al., “Gene targeting using zinc finger nucleases,” [cited by applicant]
Pâques et al., “Meganucleases and DNA Double-Strand Break-Induced Recombination: Perspectives for Gene Therapy,” [cited by applicant]
Ren et al., “Multiplex genome editing to generate universal Car T cells resistant to PD1 inhibition,” [cited by applicant]
Robbins et al., “Tumor Regression in Patients With Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1,” [cited by applicant]
Robins et al., “Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells,” [cited by applicant]
Robins et al., “Overlap and effective size of the human CD8+ T-cell receptor repertoire,” [cited by applicant]
Robins et al., “Ultra-sensitive detection of rare T cell clones,” [cited by applicant]
Sadelain et al., “The basic principles of chimeric antigen receptor (CAR) design,” [cited by applicant]
Salter et al., “Impaired assembly and transport of HLA-A and -B antigens in a mutant TxB cell hybrid,” [cited by applicant]
Schmied et al., “Analysis of the functional WT1-specific T-cell repertoire in healthy donors reveals a discrepancy between CD4 [cited by applicant]
Schmitt et al., “Generation of TCRs of higher affinity by antigen-driven differentiation of progenitor T cells in vitro,” [cited by applicant]
Schmitt et al., “T Cell Receptor Gene Therapy for Cancer,” [cited by applicant]
Scholten et al., “Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells,” [cited by applicant]
Stone et al., “A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control,” [cited by applicant]
Stone et al., “Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies,” [cited by applicant]
Straathof et al., “An inducible caspase 9 safety switch for T-cell therapy,” [cited by applicant]
Stromnes et al., “Abrogation of SHP-1 in tumor-specific T cells improves efficacy of adoptive immunotherapy by enhancing the effector function and accumulation of short-lived effector T cells in vivo,” [cited by applicant]
Sussman et al., “Isolation and Characterization of New Homing Endonuclease Specificites at Individual Target Site Positions,” [cited by applicant]
Terentis et al., “The Selenazal Drug Ebselen Potently Inhibits Indoleamine 2,3-Dioxygenase by Targeting Enzyme Cysteine Residues,” [cited by applicant]
Thompson et al., “cis-Acting Sequences Required for Inducible Interleukin-2 Enhancer Function Bind a Novel Ets-Related Protein, Elf-1,” [cited by applicant]
Till et al., “Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells,” [cited by applicant]
Todd et al., “Transcription of the Interleukin 4 Gene Is Regulated by Multiple Promoter Elements,” [cited by applicant]
Torikai et al., “A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR,” [cited by applicant]
Torikai et al., “Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application,” [cited by applicant]
Torikai et al., “Toward eliminating HLA class I expression to generate universal cells from allogeneic donors,” [cited by applicant]
Tsuta et al., “Comparison of Different Clones (WT49 Versus 6F-H2) of WT-1 Antibodies for Immunohistochemical Diagnosis of Malignant Pleural Mesothelioma,” [cited by applicant]
Viola et al., “T Cell Activation Determined by T Cell Receptor Number and Tunable Thresholds,” [cited by applicant]
Walseng et al., “A TCR-based Chimeric Antigen Receptor,” [cited by applicant]
Wang et al., “A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells,” [cited by applicant]
Wang et al., “Optimizing Adoptive Polyclonal T Cell Immunotherapy of Lymphomas, Using a Chimeric T Cell Receptor Possessing CD28 and CD137 Costimulatory Domains,” [cited by applicant]
Warren et al., “Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes,” [cited by applicant]
Wolfe et al., “Analysis of Zinc Fingers Optimized via Phage Display: Evaluating the Utility of a Recognition Code,” [cited by applicant]
Xie et al., “sgRNAcas9: A Software Package for Designing CRISPR sgRNA and Evaluating Potential Off-Target Cleavage Sites,” [cited by applicant]
Zhou et al., “Improving the Safety of T Cell Therapies using an Inducible Caspase-9 Gene,” [cited by applicant]
Ashouri et al., “Endogenous Nur77 Is a Specific Indicator of Antigen Receptor Signaling in Human T and B Cells,” [cited by applicant]
Chapuis et al., “T Cell Receptor Gene Therapy Targeting WTI Prevents Acute Myeloid Leukemia Relapse Post-Transplant,” [cited by applicant]
Cohen et al., “Enhanced Antitumor Activity of T Cells Engineered to Express T-Cell Receptors with a Second Disulfide Bond,” [cited by applicant]
Cole et al., “The molecular determinants of CD8 co-receptor function,” [cited by applicant]
Dunbar et al., “ANARCI: antigen receptor numbering and receptor classification,” [cited by applicant]
Engels et al., “Retroviral Vectors for High-Level Transgene Expression in T Lymphocytes,” [cited by applicant]
Frecha et al., “Advances in the Field of Lentivector-based Transduction of T and B Lymphocytes for Gene Therapy,” [cited by applicant]
Gaiger et al., “WT1-specific Serum Antibodies in Patients with Leukemia,” [cited by applicant]
Hu et al., “Immune Signature of Enhanced Functional Avidity CD8+ T Cells in vivo Induced by Vaccinia Vectored Vaccine,” [cited by applicant]
IMGT, “IMGT Repertoire (IG and TR),” retrieved at URL=imgt.org/IMGTrepertoire/LocusGenes/listIG_TR/TR/human/Hu_TRgroup.html, last updated Sep. 22, 2023. (1 page). [cited by applicant]
Inoue et al., “WTI as a New Prognostic Factor and a New Marker for the Detection of Minimal Residual Disease in Acute Leukemia,” [cited by applicant]
International Search Report, dated Feb. 3, 2021, for International Patent Application No. PCT/US2020/047071. (8 pages). [cited by applicant]
Kennedy et al., “Multiple roles for CD4+ T cells in anti-tumor immune responses,” [cited by applicant]
Krisky et al., “Development of herpes simplex virus replicationdefective multigene vectors for combination gene therapy applications,” [cited by applicant]
Liebl et al., “Transfer of [cited by applicant]
Nakanishi et al., “CTL mobilization to virus-infected tissue requires CD4+ T cell help,” [cited by applicant]
Ogawa et al., “The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia,” [cited by applicant]
Richman et al., “Display, engineering, and applications of antigen-specific T cell receptors,” [cited by applicant]
Scatchard et al., “The Attractions of Proteins for Small Molecules and Ions,” [cited by applicant]
Seeliger et al., “Boosting antibody developability through rational sequence optimization,” [cited by applicant]
Udyavar et al., “Subtle Affinity-Enhancing Mutations in a Myelin Oligodendrocyte Glycoprotein-Specific TCR Alter Specificity and Generate New Self-Reactivity,” [cited by applicant]
Verhoeyen et al., “Chapter 8: Lentiviral Vector Gene Transfer into Human T Cells,” [cited by applicant]
Viganò et al., “Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?,” [cited by applicant]
Wälchli et al., “A Practical Approach to T-Cell Receptor Cloning and Expression,” [cited by applicant]
Walseng et al., “Soluble T-Cell Receptors Produced in Human Cells for Targeted Delivery,” [cited by applicant]
Wilson, “Analyzing Biomolecular Interactions,” [cited by applicant]
Wolff et al., “Monoclonal Antibody Homodimers: Enhanced Antitumor Activity in Nude Mice,” [cited by applicant]
Zhao et al., “High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines,” [cited by applicant]
Zhao et al., “Primary Human Lymphocytes Transduced with NY-ESO-1 Antigen-Specific TCR Genes Recognize and Kill Diverse Human Tumor Cell Lines,” [cited by applicant]