Granted Patent
B2
US 12,188,048 · App. 17/819,909 · Granted Jan 7, 2025
Restimulation of cryopreserved tumor infiltrating lymphocytes
Assignee:
IOVANCE BIOTHERAPEUTICS, INC.
C12N5/0636A01N1/0284A61K39/4611A61K39/46449A61P35/00C07K14/7051C07K16/00C12N15/85G01N33/5005A61K2239/57C07K2317/24C07K2319/03C07K2319/33C12N2501/04C12N2501/2302C12N2502/11C12N2502/1121C12N2502/99
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Abstract
The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation.
Claims (26)
1. A population of expanded tumor infiltrating lymphocytes (TILs), wherein the population of expanded TILs is a third population of TILs obtainable by a method comprising:
(a) performing a first expansion by (i) thawing cryopreserved dissociated tumor materials comprising a first population of TILs obtained from a tumor that was resected from a subject with cancer, and (ii) culturing the first population of TILs in a cell culture medium comprising IL-2 to produce a second population of TILs;
(b) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the third population of TILs is a therapeutic population of TILs, and wherein the second expansion is performed for about 7 to 11 days before being split into more than one container or flask in order to obtain the third population of TILs; and
(c) harvesting the third population of TILs obtained from step (b).
2. The population of expanded TILs according to claim 1 , wherein the method further comprises a step (d) of transferring the harvested third population of TILs from step (c) into an infusion bag.
3. The population of expanded TILs according to claim 2 , wherein the method further comprises a step (e) of cryopreserving the infusion bag comprising the harvested TIL population from step (d) using a cryopreservation process.
4. The population of expanded TILs according to claim 1 , wherein the dissociated tumor materials comprise a tumor digest.
5. The population of expanded TILs according to claim 1 , wherein obtaining the dissociated tumor materials comprises fragmenting the tumor resected from the subject into one or more tumor fragments.
6. The population of expanded TILs according to claim 1 , wherein obtaining the dissociated tumor materials comprises mechanically disrupting the tumor resected from the subject.
7. The population of expanded TILs according to claim 1 , wherein obtaining the dissociated tumor materials comprises enzymatically disrupting the tumor resected from the subject.
8. The population of expanded TILs according to claim 1 , wherein the third population of TILs harvested in step (c) comprises sufficient TILs for use in administering a therapeutically effective dosage to a subject.
9. The population of expanded TILs according to claim 8 , wherein the therapeutically effective dosage of TILs comprises from about 1×10 9 to about 9×10 10 TILs.
10. The population of expanded TILs according to claim 1 , wherein the APCs comprise peripheral blood mononuclear cells (PBMCs).
11. The population of expanded TILs according to claim 1 , wherein step (a) further comprises adding the thawed dissociated tumor materials into a closed system prior to culturing the first population of TILs.
12. The population of expanded TILs according to claim 11 , wherein the transition from step (a) to step (b), the transition from step (b) to step (c), or the transition from step (c) to step (d) occurs without opening the system.
13. The population of expanded TILs according to claim 1 , wherein step (a) further comprises adding the thawed dissociated tumor materials into a closed system prior to culturing the first population of TILs, wherein the transition from step (a) to step (b) occurs without opening the system, and wherein the transition from step (b) to step (c) occurs without opening the system.
14. The population of expanded TILs according to claim 1 , wherein the first expansion is performed within from about 11 to 21 days.
15. The population of expanded TILs according to claim 1 , wherein the first expansion is performed within about 11 days, 12 days, 13 days or 14 days.
16. The population of expanded TILs according to claim 1 , wherein the second expansion is performed for about 7 days, 8 days, 9 days, 10 days or 11 days before being split into more than one container or flask.
17. The population of expanded TILs according to claim 1 , wherein the second expansion is performed for about 7 days before being split into more than one container or flask.
18. The population of expanded TILs according to claim 1 , wherein the second expansion is performed within about 8 days before being split into more than one container or flask.
19. The population of expanded TILs according to claim 1 , wherein steps (a) through (c) are performed within about 24 days.
20. The population of expanded TILs according to claim 1 , wherein the cryopreserved dissociated tumor materials were obtained by cryopreserving dissociated tumor materials in a cryopreservation media comprising DMSO.
21. The population of expanded TILs according to claim 20 , wherein the cryopreservation media comprises 5% DMSO.
22. The population of expanded TILs according to claim 1 , wherein the cancer is selected from the group consisting of: melanoma, cervical cancer, head and neck cancer, glioblastoma, ovarian cancer, sarcoma, pancreatic cancer, bladder cancer, breast cancer, triple negative breast cancer, and non-small cell lung carcinoma.
23. The population of expanded TILs according to claim 1 , wherein the cancer is melanoma.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Oct 27, 2022
From: FRANK, IAN; LOTZE, MICHAEL T.
To: LION BIOTECHNOLOGIES, INC.
Reel/Frame 061567/0271 →
CHANGE OF NAME
Recorded Oct 27, 2022
From: LION BIOTECHNOLOGIES, INC.
To: IOVANCE BIOTHERAPEUTICS, INC.
Reel/Frame 061793/0296 →
Continuity (11)
Continuation
15751440
Provisional Application
62415452
· Oct 31, 2016
Provisional Application
62413387
· Oct 26, 2016
Provisional Application
62413283
· Oct 26, 2016
References Cited (307)
US 4766106A
· Katre et al.
· 1988
[cited by applicant]
US 4902502A
· Nitecki et al.
· 1990
[cited by applicant]
US 5089261A
· Nitecki et al.
· 1992
[cited by applicant]
US 5126132A
· Rosenberg
· 1992
[cited by applicant]
US 5206344A
· Katre et al.
· 1993
[cited by applicant]
US 5443983A
· Ochoa et al.
· 1995
[cited by applicant]
US 6352694B1
· June et al.
· 2002
[cited by applicant]
US 6534055B1
· June et al.
· 2003
[cited by applicant]
US 6706289B2
· Lewis et al.
· 2004
[cited by applicant]
US 6867041B2
· Berenson et al.
· 2005
[cited by applicant]
US 6887466B2
· June et al.
· 2005
[cited by applicant]
US 6905680B2
· June et al.
· 2005
[cited by applicant]
US 6905681B1
· June et al.
· 2005
[cited by applicant]
US 7144575B2
· June et al.
· 2006
[cited by applicant]
US 7175843B2
· June et al.
· 2007
[cited by applicant]
US 7232566B2
· June et al.
· 2007
[cited by applicant]
US 7479269B2
· June et al.
· 2009
[cited by applicant]
US 7572631B2
· Berenson et al.
· 2009
[cited by applicant]
US 7943743B2
· Korman et al.
· 2011
[cited by applicant]
US 7951365B2
· Winqvist et al.
· 2011
[cited by applicant]
US 8007785B2
· Winqvist et al.
· 2011
[cited by applicant]
US 8008449B2
· Korman et al.
· 2011
[cited by applicant]
US 8034334B2
· Dudley et al.
· 2011
[cited by applicant]
US 8206702B2
· Winqvist et al.
· 2012
[cited by applicant]
US 8211424B2
· Winqvist et al.
· 2012
[cited by applicant]
US 8211425B2
· Winqvist et al.
· 2012
[cited by applicant]
US 8287857B2
· Dudley et al.
· 2012
[cited by applicant]
US 8383099B2
· Dudley et al.
· 2013
[cited by applicant]
US 8617884B2
· Berenson et al.
· 2013
[cited by applicant]
US 8809050B2
· Vera et al.
· 2014
[cited by applicant]
US 8956860B2
· Vera et al.
· 2015
[cited by applicant]
US 9074185B2
· Dudley et al.
· 2015
[cited by applicant]
US 9476028B2
· Karlsson-Parra et al.
· 2016
[cited by applicant]
US 9528088B2
· Berenson et al.
· 2016
[cited by applicant]
US 9687510B2
· Borrello et al.
· 2017
[cited by applicant]
US 9844569B2
· Gros et al.
· 2017
[cited by applicant]
US 9914783B1
· Afar et al.
· 2018
[cited by applicant]
US 20120244133A1
· Rosenberg et al.
· 2012
[cited by applicant]
US 20130115617A1
· Wilson
· 2013
[cited by applicant]
US 20150320798A1
· Borrello et al.
· 2015
[cited by applicant]
US 20160010058A1
· Gros et al.
· 2016
[cited by applicant]
US 20160208216A1
· Vera et al.
· 2016
[cited by applicant]
US 20170044496A1
· Sarnaik et al.
· 2017
[cited by applicant]
US 20170081635A1
· Sarnaik et al.
· 2017
[cited by applicant]
US 20170107490A1
· Maeurer
· 2017
[cited by applicant]
US 20170114321A1
· Berenson et al.
· 2017
[cited by applicant]
US 20170152478A1
· Rosenberg et al.
· 2017
[cited by applicant]
US 20180187150A1
· De Larichaudy
· 2018
[cited by applicant]
US 20190062706A1
· Almaasbak et al.
· 2019
[cited by applicant]
CN 102816734A
· 2012
[cited by applicant]
CN 106244538A
· 2016
[cited by applicant]
CN 106591232A
· 2017
[cited by applicant]
CN 107384867A
· 2017
[cited by applicant]
EP 1539929B1
· 2013
[cited by applicant]
EP 2925329A1
· 2015
[cited by applicant]
EP 3188740A1
· 2017
[cited by applicant]
EP 3365434A1
· 2018
[cited by applicant]
EP 3368659A1
· 2018
[cited by applicant]
EP 3487990A1
· 2019
[cited by applicant]
WO WO2004031370A1
· 2004
[cited by applicant]
WO WO2009040789A2
· 2009
[cited by applicant]
WO WO2011072088A2
· 2011
[cited by applicant]
WO WO2012065086A1
· 2012
[cited by applicant]
WO WO2012129201A1
· 2012
[cited by applicant]
WO WO2013057500A1
· 2013
[cited by applicant]
WO WO2013088147A1
· 2013
[cited by applicant]
WO WO2013173835A1
· 2013
[cited by applicant]
WO WO2013188427A1
· 2013
[cited by applicant]
WO WO2014210036A1
· 2014
[cited by applicant]
WO WO2015009604A1
· 2015
[cited by applicant]
WO WO2015157636A1
· 2015
[cited by applicant]
WO WO2015188839A1
· 2015
[cited by applicant]
WO WO2015189356A1
· 2015
[cited by applicant]
WO WO2015189357A1
· 2015
[cited by applicant]
WO WO2016053338A1
· 2016
[cited by applicant]
WO WO2016096903A1
· 2016
[cited by applicant]
WO WO2017048614A1
· 2017
[cited by applicant]
WO WO2018005712A1
· 2018
[cited by applicant]
WO WO2018081473A1
· 2018
[cited by applicant]
WO WO2018102761A1
· 2018
[cited by applicant]
WO WO2018129332A1
· 2018
[cited by applicant]
WO WO2018170188A2
· 2018
[cited by applicant]
WO WO2018182817A1
· 2018
[cited by applicant]
WO WO2018209115A1
· 2018
[cited by applicant]
WO WO2018226714A1
· 2018
[cited by applicant]
U.S. Appl. No. 17/856,800, filed Jul. 1, 2022, now allowed.
[cited by applicant]
U.S. Appl. No. 17/817,207, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,279, filed Aug. 3, 2022, now allowed.
[cited by applicant]
U.S. Appl. No. 17/817,266, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,281, filed Aug. 3, 2022, now allowed.
[cited by applicant]
Wu, Richard et al. “Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook.” Cancer journal (Sudbury, Mass.) vol. 18,2 (2012): 160-75. doi:10.1…
[cited by applicant]
U.S. Appl. No. 17/856,800, filed Jul. 1, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,276, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,279, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,226, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,281, filed Aug. 3, 2022.
[cited by applicant]
Akkök, C. A et al. “Use of different DMSO concentrations for cryopreservation of autologous peripheral blood stem cell grafts does not have any major impact on levels of leukocyte- and platelet-derived soluble mediators…
[cited by applicant]
Andersen, Rikke et al. “Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.” Clinical cancer research : an …
[cited by applicant]
Axelsson et al., “Cryopreserved peripheral blood mononuclear cells are suitable for the assessment of immunological markers in type 1 diabetic children”, Cryobiology, Aug. 2008, 57, 201-208.
[cited by applicant]
Bajgain, P. et al., “Optimizing the production of suspension cells using the G-Rex “M” series”, Molecular Therapy—Methods and Clinical Development, vol. 1, Jan. 1, 2014.
[cited by applicant]
Baruch et al., “Adoptive T cell therapy: An overview of obstacles and opportunities : ACT Obstacles and Opportunities”, Cancer, vol. 123, No. S11, May 19, 2017, pp. 2154-2162.
[cited by applicant]
Besser et al., “Minimally Cultured or Selected Autologous Tumor-infiltrating Lymphocytes After a Lympho-depleting Chemotherapy Regimen in Metastatic Melanoma Patients”; J Immunother 32, 415-423 (2009).
[cited by applicant]
Besser, et al., “Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies”; Clin Cancer Res, 19(17):0F1-0F9 (…
[cited by applicant]
Besser, Michal J et al. “Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients.” Clinical cancer research : an official jour…
[cited by applicant]
Chacon et al., “Co-stimulation through 4-1BB/CD137 Improves the Expansion and Fundtion of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy”, PLOS One, vol. 8, No. 4, Apr. 1, 2013, 25 pages.
[cited by applicant]
Chang C.-H. et al., “Metabolic competition in the tumor microenvironment is a driver of cancer progression”, Cell., Sep. 10, 2015, vol. 162, No. 6, pp. 1229-1241.
[cited by applicant]
Chang et al., “Emerging concepts in immunotherapy T-cell metabolism as a therapeutic target”, Nat. Immunol., Apr. 2016, 17(4), 364-368.
[cited by applicant]
Donia, M et al., “Characterization and comparison of ‘standard’ and ‘young’ tumour-infiltrating lymphocytes for adoptive cell therapy at a Danish translational research institution.” Scandinavian journal of immunology v…
[cited by applicant]
Donia, M, et al.. “Simplified protocol for clinical-grade tumor-infiltrating lymphocyte manufacturing with use of the Wave bioreactor”, Cytotherapy. Aug. 2014;16(8):1117-20. doi: 10.1016/j.jcyt.2014.02.004; PubMed PMID:…
[cited by applicant]
Dudley et al., “CD8+ Enriched “Young” Tumor Infiltrating Lymphocytes Can Mediate Regression of Metastatic Melanoma” Clin Cancer Res, 16:6122-6131 (2010).
[cited by applicant]
Dudley et al., “Generation of Tumor-Infiltrating Lymphocyte Cultures for Use in Adoptive Transfer Therapy for Melanoma Patients,” J Immunother., 2003: 26(4): 332-342.
[cited by applicant]
Dudley, et al., “Adoptive Cell Therapy for Patients with Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens”, J. Clin. Oncol., Nov. 2008, 26(32), 5233-39.
[cited by applicant]
Dudley, et al., “Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes”, Science, Oct. 2002, 298, 850-54.
[cited by applicant]
Dudley, et at., “Adoptive Cell Transfer Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients with Refractory Metastatic Melanoma”, J. Clin. Oncol. Apr. 2005, 23(10), 2346-57.
[cited by applicant]
Forget et al., “Activation and propagation of tumor infiltrating lymphocytes on clinical-grade designer artificial antigen presenting cells for adoptive immunotherapy of melanoma”, Journal of Immunotherapy, vol. 37 No. …
[cited by applicant]
Forget, Marie-Andrée et al. “The beneficial effects of a gas-permeable flask for expansion of Tumor-Infiltrating lymphocytes as reflected in their mitochondrial function and respiration capacity.” Oncoimmunology vol. 5,…
[cited by applicant]
Frank et al., “Remarkably Stable Tumor-Infiltrating Lymphocytes (TIL) for Infusion Phenotype Following Cryopreservation”, Nov. 6, 2016, Retrieved from the Internet: http://www.iovance.com/wp-content/uploads/2017/05/LION…
[cited by applicant]
Garaud, Soizic et al. “A simple and rapid protocol to non-enzymatically dissociate fresh human tissues for the analysis of infiltrating lymphocytes.” Journal of visualized experiments : JoVE ,94 52392. Dec. 6, 2014, doi…
[cited by applicant]
Gassner, et al., “Fludarabine modulates composition and function of the T Cell pool in patients with chronic lymphocytic leukaemia”, Cancer. Immunol. Immunother., 2011, 60, 75-85.
[cited by applicant]
Gattinoni, et al., “Adoptive immunotherapy for cancer: building on success”, Nat. Rev. Immunol. May 2006, 6(5), 383-393.
[cited by applicant]
Gladstone, D E et al. “Infusion of cryopreserved autologous lymphocytes using a standard peripheral i.v. catheter.” Bone marrow transplantation vol. 49,8 (2014): 1119-20. doi:10.1038/bmt.2014.98.
[cited by applicant]
Glassman, A B, and C E Bennett. “Cryopreservation of human lymphocytes: a brief review and evaluation of an automated liquid nitrogen freezer.” Transfusion vol. 19,2 (1979): 178-81. doi:10.1046/j.1537-2995.1979.19279160…
[cited by applicant]
Goff et al., “Tumor Infiltrating Lymphocyte Therapy for Metastatic Melanoma: Analysis of Tumors Resected for TIL”, J. Immunother, Oct. 2010, 33(8), 840-847.
[cited by applicant]
Goff SL, et al., “Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma”, J Clin Oncol. Jul. 10, 2016;…
[cited by applicant]
Hall et al., “Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors”, Journal for ImmunoTherapy of Cancer, vol. 4, No. 1, pp. 1-12.
[cited by applicant]
Hasan et al., “Artificial Antigen Presenting Cells: An Off the Shelf Approach for Generation of Desirable T-Cell Populations for Broad Application of Adoptive Immunotherapy”, Adv Genet Eng, 2015, 4:3.
[cited by applicant]
Henning AL, et al.. Measurement of T-Cell Telomere Length Using Amplified-Signal FISH Staining and Flow Cytometry. Curr Protoc Cytom. Jan. 5, 2017;79:7.47.1-7.47.10. doi: 10.1002/cpcy.11. PubMed PMID 28055115.
[cited by applicant]
Hernandez-Chacon et al., “Costimulation through the CD137/4-1BB Pathway Protects Human Melanoma Tumor-infiltrating Lymphocytes from Activation-induced Cell Death and Enhances Antitumor Effector Function”, Journal of Imm…
[cited by applicant]
Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. Jan. 2014;257(1):56-71. doi:10.1111/imr.12132. Review. PubMed PMID: 24329789; PubMed Central PMCID: PMC392…
[cited by applicant]
Huang et al., “Survival, Persistence, and Progressive Differentiation of Adoptively Transferred Tumor-Reactive T Cells Associated with Tumor Regression”; J. Immunother, 28(3), 258-267 (2005).
[cited by applicant]
Ikarashi, H et al., “Solid-phase anti-CD3 antibody activation and cryopreservation of human tumor-infiltrating lymphocytes derived from epithelial ovarian cancer”, Japanese Journal of Cancer Research, vol. 83, No. 12, D…
[cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2017/058610 dated Mar. 8, 2018, 13 pages.
[cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2018/012633 dated May 25, 2018, 14 pages.
[cited by applicant]
International Search Report and Written Opinion for International Patent Application No. PCT/US2018/040474 dated Nov. 14, 2018, 17 pages.
[cited by applicant]
Itzhaki, Orit et al. “Establishment and large-scale expansion of minimally cultured “young” tumor infiltrating lymphocytes for adoptive transfer therapy.” Journal of immunotherapy (Hagerstown, Md. : 1997) vol. 34,2 (201…
[cited by applicant]
Iyer, R.K. et al., “Industrializing Autologous Adoptive Immunotherapies: Manufacturing Advances and Challenges”, Frontiers in Medicine, vol. 5, May 23, 2018.
[cited by applicant]
Jia HE et al., “Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy,” Chinese Journal of Cancer, vol. 31, No. 6, Jun. 5, 2012.
[cited by applicant]
Jin et al., “Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules”, Journal of Transactional Medicine, col. 16. No. 1, Jan. 24, 2018.
[cited by applicant]
Jin et al., “Simplified method of the growth of human tumor infiltrating lymphocytes in gas-permiable flasks to numbers needed for patient treatment”, J. Immunotherapy, 2012, 35:283-292.
[cited by applicant]
Junker, Niels et al. “Bimodal ex vivo expansion of T cells from patients with head and neck squamous cell carcinoma: a prerequisite for adoptive cell transfer.” Cytotherapy vol. 13,7 (2011): 822-34. doi:10.3109/14653249…
[cited by applicant]
Klapper, J.A. et al., “Single-pass, closed-system rapid expansion of lymphocyte cultures for adoptive cell therapy”, Journal of Immunological Methods, vol. 345, No. 1-2, Jun. 30, 2009.
[cited by applicant]
Lee et al., “Tumor-Infiltrating Lymphocytes in Melanoma”, Curr Oncol Rep. Aug. 2012, 14, 468-474.
[cited by applicant]
Li et al. MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. J Immunol. Jan. 1, 2010;184(1):45…
[cited by applicant]
Merhavi-Shoham et al., “Adoptive Cell Therapy for Metastatic Melanoma”, Cancer Journal, vol. 23, No. 1, Jan. 1, 2017.
[cited by applicant]
Mullinax et al., “Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma”, Frontiers in Oncology, vol. 8, Mar. 2, 2018.
[cited by applicant]
Muranski, et al., “Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go?”, Nat. Clin. Pract. Oncol., Dec. 2006, 3, 668-681.
[cited by applicant]
Nguyen, Linh T et al. “Expansion and characterization of human melanoma tumor-infiltrating lymphocytes (TILs).” PloS one vol. 5,11 e13940. Nov. 10, 2010, doi:10.1371/journal.pone.0013940.
[cited by applicant]
Riddell, et al., “Restoration of Viral Immunity in Immunodeficient Humans by the Adoptive Transfer of T Cell Clones”, Science, Jul. 1992, 257, 238-41.
[cited by applicant]
Robbins, et al., “Cutting Edge: Persistence of Transferred Lymphocyte Clonotypes Correlates with Cancer Regression in Patients Receiving Cell Transfer Therapy”; J. Immunol 2004; 173, 7125-7130.
[cited by applicant]
Rohaan et al., “Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option”, Journal for Immunotherapy of Cancer, vol. 6, No. 1, Oct. 3, 2018, pp. 1-16.
[cited by applicant]
Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. Apr. 2009;21(2):233-40.
[cited by applicant]
Rosenberg SA, et al. “Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T Cell Transfer Immunotherapy”, Clinical Cancer research, vol. 17, No. 13, Jul. 1, 2011 pp. 4550-4557.
[cited by applicant]
Rosenberg, “IL-2: The First Effective Immunotherapy for Human Cancer,” The Journal of Immunology, col. 192, No. 12, Jun. 6, 2014.
[cited by applicant]
Rosenberg, S A et al. “A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.” Science (New York, N.Y.) vol. 233,4770 (1986): 1318-21. doi:10.1126/science.3489291.
[cited by applicant]
Rosenberg, S A et al. “Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.” Journal of the National Cancer Institute vol. 86,15 (1994): 1159-66. doi:10.1093/j…
[cited by applicant]
Rosenberg, S A et al. “Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.” The New England journal of medicine vol. 319,25 (1988): 16…
[cited by applicant]
Rufer N, et al., “Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry”, Nat Biotechnol. Aug. 1998;16(8):743-7. PubMed PMID: 9702772.
[cited by applicant]
Sadeghi, et al., “Rapid expansion of T cells: Effects of culture and cryopreservation and improtance of short-term cell recovery”, Acta Oncologica 2013, 52, 978-986.
[cited by applicant]
Schiltz, P M et al. “Characterization of tumor-infiltrating lymphocytes derived from human tumors for use as adoptive immunotherapy of cancer.” Journal of immunotherapy (Hagerstown, Md. : 1997) vol. 20,5 (1997): 377-86.…
[cited by applicant]
Shen X, et al.. Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length. J Immunother. Jan. 2007;30(1):123-9. PubMed PMID:17198091; PubMed Central PMCID: PMC2151201.
[cited by applicant]
Somerville RP, et al.. Clinical scale rapid expansion of lymphocytes for adoptive cell transfer therapy in the WAVE® bioreactor. J Transl Med. Apr. 4, 2012;10:69.
[cited by applicant]
Spiess, P J et al. “In vivo antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2.” Journal of the National Cancer Institute vol. 79,5 (1987): 1067-75.
[cited by applicant]
Tran et al., “Minimally Cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy”, 2008, J. Immunother., Oct. 2008 31 (8), 742-751.
[cited by applicant]
Tsoukas et al., “Activation of resting T lymphocytes by anti-CD3 (T3) antibodies in the absence of monocytes”, J. Immunol. 1985, 135, 1719.
[cited by applicant]
Van den Bossche, J. et al. “Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis.” Journal of visualized experiments : JoVE ,105 53424. Nov. 28, 2…
[cited by applicant]
Wang & Riviere, “Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies”, Cancer Gene Therapy, 2015, 22: 85-94.
[cited by applicant]
Wardell et al., “A cryopreserved tumor infiltrating lymphocyte (TIL) product for LN-44”, Nov. 8, 2017, retrieved from the Internet: URL: http://www.iovance.com/wp-content/uploads/2017/11/SITC2017_Seth_poster_FINAL_SWDE_…
[cited by applicant]
Wilson Wolf—Superior Cell Culture Devices, G-Rex, Oct. 31, 2016.
[cited by applicant]
Ye, et al., “Engineered Artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes”, J. Translat. Med. 2011, 9(131), 13 pages.
[cited by applicant]
Zhou J, et al.. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol. Nov. 15, 2005;175(10):7046-52. PubMed …
[cited by applicant]
Zhou, et al., “Persistence of Multiple Tumor-Specific T-Cell Clones Is Associated with Complete Tumor Regression in a Melanoma Patient Receiving Adoptive Cell Transfer Therapy”; J. Immunother, 28, 53-62 (2005).
[cited by applicant]
Zuliani, T. et al., “Value of large scale expansion of tumor infiltrating lymphocytes in a compartmentalised gas-permiable bag: interests for adoptive immunotherapy”, Journal of Translational Medicine, vol. 9, No. 1, Ma…
[cited by applicant]
U.S. Appl. No. 15/863,634, filed Jan. 5, 2018, now U.S. Pat. No. 10,894,063.
[cited by applicant]
U.S. Appl. No. 15/874,718, filed Jan. 18, 2018, now U.S. Pat. No. 10,166,257.
[cited by applicant]
U.S. Appl. no. 15/892,311, filed Feb. 8, 2018, now U.S. Pat. No. 10,130,659.
[cited by applicant]
U.S. Appl. No. 16/136,147, filed Sep. 19, 2018, now U.S. Pat. No. 10,272,113.
[cited by applicant]
U.S. Appl. No. 16/136,157, filed Sep. 19, 2018, now U.S. Pat. No. 10,420,799.
[cited by applicant]
U.S. Appl. No. 16/201,957, filed Nov. 27, 2018, now U.S. Pat. No. 10,398,734.
[cited by applicant]
U.S. Appl. No. 16/192,707, filed Nov. 15, 2018, now U.S. Pat. No. 10,537,595.
[cited by applicant]
U.S. Appl. No. 16/425,746, filed May 29, 2019, now U.S. Pat. No. 10,639,330.
[cited by applicant]
U.S. Appl. No. 16/203,467, filed Nov. 28, 2018, now U.S. Pat. No. 10,463,697.
[cited by applicant]
U.S. Appl. No. 16/203,478, filed Nov. 28, 2018, now U.S. Pat. No. 10,363,273.
[cited by applicant]
U.S. Appl. No. 16/425,767, filed May 29, 2019, now U.S. Pat. No. 10,695,372.
[cited by applicant]
U.S. Appl. No. 16/425,778, filed May 29, 2019, now U.S. Pat. No. 10,646,517.
[cited by applicant]
U.S. Appl. No. 16/746,416, filed Jan. 17, 2020, now U.S. Pat. No. 10,653,723.
[cited by applicant]
U.S. Appl. No. 16/848,361, filed Apr. 14, 2020, now U.S. Pat. No. 10,905,718.
[cited by applicant]
U.S. Appl. No. 16/848,386, filed Apr. 14, 2020, now U.S. Pat. No. 10,953,046.
[cited by applicant]
U.S. Appl. No. 16/848,454, filed Apr. 14, 2020, now U.S. Pat. No. 10,946,044.
[cited by applicant]
U.S. Appl. No. 16/848,426, filed Apr. 14, 2020, now U.S. Pat. No. 10,953,047.
[cited by applicant]
U.S. Appl. No. 16/848,442, filed Apr. 14, 2020, now U.S. Pat. No. 10,933,094.
[cited by applicant]
U.S. Appl. No. 16/848,474, filed Apr. 14, 2020, now U.S. Pat. No. 10,946,045.
[cited by applicant]
U.S. Appl. No. 16/879,711, filed May 20, 2020, now U.S. Pat. No. 10,925,900.
[cited by applicant]
U.S. Appl. No. 17/110,207, filed Dec. 2, 2020, now U.S. Pat. No. 11,083,752.
[cited by applicant]
U.S. Appl. No. 17/127,768, filed Dec. 18, 2020, now U.S. Pat. No. 11,007,225.
[cited by applicant]
U.S. Appl. No. 17/127,840, filed Dec. 18, 2020, now U.S. Pat. No. 11,052,116.
[cited by applicant]
U.S. Appl. No. 17/127,790, filed Dec. 18, 2020, now U.S. Pat. No. 11,007,226.
[cited by applicant]
U.S. Appl. No. 17/127,795, filed Dec. 18, 2020, now U.S. Pat. No. 11,052,115.
[cited by applicant]
U.S. Appl. No. 17/147,073, filed Jan. 12, 2021, now U.S. Pat. No. 11,013,770.
[cited by applicant]
U.S. Appl. No. 17/147,080, filed Jan. 12, 2021.
[cited by applicant]
U.S. Appl. No. 17/147,090, filed Jan. 12, 2021, now U.S. Pat. No. 11,040,070.
[cited by applicant]
U.S. Appl. No. 17/147,096, filed Jan. 12, 2021.
[cited by applicant]
U.S. Appl. No. 17/326,088, filed May 20, 2021, now U.S. Pat. No. 11,202,803.
[cited by applicant]
U.S. Appl. No. 17/382,831, filed Jul. 22, 2021, now U.S. Pat. No. 11,241,456.
[cited by applicant]
U.S. Appl. No. 17/383,272, filed Jul. 22, 2021, now U.S. Pat. No. 11,202,804.
[cited by applicant]
U.S. Appl. No. 17/383,276, filed Jul. 22, 2021, now U.S. Pat. No. 11,273,180.
[cited by applicant]
U.S. Appl. No. 17/383,280, filed Jul. 22, 2021, now U.S. Pat. No. 11,304,979.
[cited by applicant]
U.S. Appl. No. 17/480,525, filed Sep. 21, 2021, now U.S. Pat. No. 11,273,181.
[cited by applicant]
U.S. Appl. No. 17/480,534, filed Sep. 21, 2021, now U.S. Pat. No. 11,291,687.
[cited by applicant]
U.S. Appl. No. 17/480,587, filed Sep. 21, 2021, now U.S. Pat. No. 11,344,579.
[cited by applicant]
U.S. Appl. No. 17/480,596, filed Sep. 21, 2021, now U.S. Pat. No. 11,337,998.
[cited by applicant]
U.S. Appl. No. 17/856,793, filed Jul. 1, 2022.
[cited by applicant]
U.S. Appl. No. 17/856,800, filed Jul. 1, 2022, now U.S. Pat. No. 11,517,592.
[cited by applicant]
U.S. Appl. No. 17/856,806, filed Jul. 1, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,207, filed Aug. 3, 2022, now allowed.
[cited by applicant]
U.S. Appl. No. 17/817,273, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,276, filed Aug. 3, 2022, now allowed.
[cited by applicant]
U.S. Appl. No. 17/817,217, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,279, filed Aug. 3, 2022, now U.S. Pat. No. 11,541,077.
[cited by applicant]
U.S. Appl. No. 17/817,226, filed Aug. 3, 2022, now allowed.
[cited by applicant]
U.S. Appl. No. 17/817,232, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,239, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 17/817,281, filed Aug. 3, 2022, now U.S. Pat. No. 11,529,372.
[cited by applicant]
U.S. Appl. No. 17/817,247, filed Aug. 3, 2022.
[cited by applicant]
U.S. Appl. No. 15/751,440, filed Feb. 8, 2018, now U.S. Pat. No. 11,026,974.
[cited by applicant]
U.S. Appl. No. 15/892,331, filed Feb. 8, 2018, now U.S. Pat. No. 10,517,894.
[cited by applicant]
U.S. Appl. No. 17/225,993, filed Apr. 8, 2021, now U.S. Pat. No. 11,058,728.
[cited by applicant]
U.S. Appl. No. 17/233,290, filed Apr. 16, 2021, now U.S. Pat. No. 11,179,419.
[cited by applicant]
U.S. Appl. No. 17/233,295, filed Apr. 16, 2021, now U.S. Pat. No. 11,123,371.
[cited by applicant]
U.S. Appl. No. 17/233,299, filed Apr. 16, 2021, now U.S. Pat. No. 11,141,438.
[cited by applicant]
U.S. Appl. No. 17/459,988, filed Aug. 27, 2021, now U.S. Pat. No. 11,304,980.
[cited by applicant]
U.S. Appl. No. 17/480,900, filed Sep. 21, 2021, now U.S. Pat. No. 11,311,578.
[cited by applicant]
U.S. Appl. No. 17/480,916, filed Sep. 21, 2021, now U.S. Pat. No. 11,351,197.
[cited by applicant]
U.S. Appl. No. 17/480,919, filed Sep. 21, 2021, now U.S. Pat. No. 11,351,198.
[cited by applicant]
U.S. Appl. No. 17/480,935, filed Sep. 21, 2021, now U.S. Pat. No. 11,344,580.
[cited by applicant]
U.S. Appl. No. 17/480,941, filed Sep. 21, 2021, now U.S. Pat. No. 11,266,694.
[cited by applicant]
U.S. Appl. No. 17/548,502, filed Dec. 11, 2021, now U.S. Pat. No. 11,364,266.
[cited by applicant]
U.S. Appl. No. 17/548,504, filed Dec. 11, 2021, now U.S. Pat. No. 11,369,637.
[cited by applicant]
U.S. Appl. No. 17/547,190, filed Dec. 9, 2021, now U.S. Pat. No. 11,344,581.
[cited by applicant]
U.S. Appl. No. 17/547,192, filed Dec. 9, 2021, now U.S. Pat. No. 11,351,199.
[cited by applicant]
U.S. Appl. No. 17/829,087, filed May 31, 2022.
[cited by applicant]
U.S. Appl. No. 17/819,209, filed Aug. 11, 2022.
[cited by applicant]
U.S. Appl. No. 17/819,214, filed Aug. 11, 2022.
[cited by applicant]
U.S. Appl. No. 17/819,219, filed Aug. 11, 2022.
[cited by applicant]
U.S. Appl. No. 17/819,909, filed Aug. 11, 2022.
[cited by applicant]
U.S. Appl. No. 17/819,910, filed Aug. 11, 2022.
[cited by applicant]
U.S. Appl. No. 15/940,901, filed Mar. 29, 2018, now U.S. Pat. No. 10,918,666.
[cited by applicant]
U.S. Appl. No. 17/041,305, filed Sep. 24, 2020.
[cited by applicant]
U.S. Appl. No. 17/110,179, filed Dec. 2, 2020.
[cited by applicant]
U.S. Appl. No. 17/147,412, filed Jan. 12, 2021.
[cited by applicant]
U.S. Appl. No. 17/148,475, filed Jan. 13, 2021, now U.S. Pat. No. 11,168,303.
[cited by applicant]
U.S. Appl. No. 17/148,508, filed Jan. 13, 2021, now U.S. Pat. No. 11,168,304.
[cited by applicant]
U.S. Appl. No. 17/353,430, filed Jun. 21, 2021, now U.S. Pat. No. 11,254,913.
[cited by applicant]
U.S. Appl. No. 17/823,445, filed Aug. 30, 2022.
[cited by applicant]
U.S. Appl. No. 17/823,448, filed Aug. 30, 2022.
[cited by applicant]
U.S. Appl. No. 17/823,454, filed Aug. 30, 2022.
[cited by applicant]
U.S. Appl. No. 17/823,419, filed Aug. 30, 2022.
[cited by applicant]
U.S. Appl. No. 16/618,039, filed Nov. 27, 2019.
[cited by applicant]
U.S. Appl. No. 16/211,159, filed Dec. 5, 2018.
[cited by applicant]
Meng, Qingda et al. “Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer.” Journal of immunotherapy (Hagerstown, Md. : 1997) vol. 39,2 (2016): 81-9. doi:1 0.1097/CJI.0000000000000111.
[cited by applicant]
Peng, Weiyi et al. “PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines.” Cancer research vol. 72,20 (2012): 5209-18. doi:10.1158/0008-5472.CAN-12-1187.
[cited by applicant]
International Preliminary Report on Patentability for International Patent Application No. PCT/US2017/058610 dated X XX XXX, 7 pages.
[cited by applicant]
Katz, Steven C et al. “Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.” Clinical cancer research : an official journal of…
[cited by applicant]
NCT03374839, ClinicalTrials.gov.
[cited by applicant]