I 1111111111111111 11111 111111111111111 111111111111111 IIIII IIIIII IIII IIII IIII
`US007402431B2
`
`c12) United States Patent
`Har-Noy
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,402,431 B2
`*Jul. 22, 2008
`
`(54) T-CELL THERAPY FORMULATION
`
`(75)
`
`Inventor: Michael Har-Noy, Modi'in (IL)
`
`(73) Assignee: Immunovative Therapies, Ltd.,
`Shoham (IL)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 160 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21)
`
`Appl. No.: 11/069,010
`
`(22)
`
`Filed:
`
`Mar.1, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2005/0214274 Al
`
`Sep.29,2005
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/549,032, filed on Mar.
`1, 2004.
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Int. Cl.
`C12N 5106
`(2006.01)
`C12N 16100
`(2006.01)
`U.S. Cl. ................................. 435/372.3; 530/391.1
`Field of Classification Search ....................... None
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,806,529 A
`6,352,694 Bl
`6,534,055 Bl
`2002/0115214 Al
`2002/0127208 Al
`2004/0228848 Al *
`
`.............. 128/898
`9/1998 Reisner et al.
`3/2002 June et al ................. 424/93.71
`3/2003 June et al ................. 424/93.71
`8/2002 June et al ................. 435/372.3
`9/2002 Waller et al .............. 424/93.21
`11/2004 Har-Noy .................. 424/93.71
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`WO 03/038062
`WO 03024989
`
`10/2002
`* 3/2003
`
`OTHER PUBLICATIONS
`
`Antin, J. H. et al. (1992). "Cytokine Dysregulation and Acute Graft(cid:173)
`Versus-Host Disease." Blood, vol. 80, No. 12: pp. 2964-2968.
`Anderson, P. et al. (1988). "Crosslinking CD3 with CD2 Using
`Sepharose-InunobilizedAntibodies Enhances T Lymphocyte Prolif(cid:173)
`eration." Cellular Immunology, vol. ll5, No. 2: pp. 246-256.
`Asselin-Paturel et al. (1998). "Quantitative Analysis ofThl, Th2 and
`TGF-f:ll Cytokine Expression in Tumor, TIL and PBL of Non-Small
`Cell Lung Cancer Patients." Int. J Cancer, vol. 77, No. 1: pp. 7-12.
`Bachmann, M. F. et al. (1997). "Distinct Roles for LFA-1 and CD28
`During Activation ofNaiveT Cells: Adhesion Versus Co stimulation."
`Immunity, vol. 7, No. 4: pp. 549-557.
`Banu, N. et al. (1999). "TGF-f:ll down-regulates induced expression
`of both class II MHC and B7-l on primary murine renal tubular
`epithelial cells." Kidney International, vol. 56, No. 3: pp. 985-994.
`Baroja, M.L. et al. (1989). "The Anti-T Cell Monoclonal Antibody
`9 .3 (Anti-CD28) Provides a Helper Signal and Bypasses the Need for
`Accessory Cells in T Cells Activation with Inunobilized Anti-CD3
`and Mitogens." Cellular Immunology, vol. 120, No. 1: pp. 205-217.
`
`Baxevanis, C. N. et al. (2000). "Compromised anti-tumor responses
`in tumor necrosis factor-a knockout mice." Eur. J Immunol., vol. 30,
`No. 7: pp. 1957-1966.
`Belardelli, F. et al. (2002). "Cytokines as a link between innate and
`adaptive antitumor inununity." Trends in Immunology, vol. 23, No. 4:
`pp. 201-208.
`Blazar, B. R. et al. (1997). "Recent advances in graft-versus-host
`disease (GVHD) prevention." Immunological Reviews, vol. 157: pp.
`79-109.
`Blazar, B. R. et al. (1998). "Rapamycin Inhibits the Generation of
`Graft-Versus-Host-Disease- and Graft-Versus-Leukemia-Causing T
`Cells by Interfering with the Production of Thl or Thl Cytotoxic
`Cytokines." Journal of Immunology, vol. 160, No. 11: pp. 5355-5365.
`Carayol, G. et al. (1997). "Quantitative Analysis of T Helper 1, T
`Helper 2, and Inflammatory Cytokine Expression in Patients After
`Allogeneic Bone Narrow Transplantation: Relationship with the
`Occurrence of Acute Graft-Versus-Host Disease." Transplantation,
`vol. 63, No. 9: pp. 1307-1313.
`Carpentier, A. F., G. Auf, et al. (2003). "CpG-oligonucleotides for
`cancer inununotherapy: review of the literature and potential appli(cid:173)
`cations in malignant glioma." Front Biosci 8: El 15-27.
`Chambers, C. A. et al. (1999). "Costimulatory regulation of T cell
`function." Current Opinion in Cell Biology, vol. ll, No. 2: pp. 203-
`210.
`Champlin, R., I. Khouri, et al. (1999). "Allogenic hematopoietic
`transplantation as adoptive inununotherapy. Induction of graft-ver(cid:173)
`sus-malignancy as primary therapy." Hematol Oneal Clin North Am
`13(5): 1041-57, vii-viii.
`Champlin, R., K. van Besien, et al. (2000). "Allogenic hematopoietic
`transplantation for chronic lymphocytic leukemia and lymphoma:
`potential for nonablative preparative regimens." Curr Oneal Rep
`2(2): 182-91.
`Chang, J. W., M. Peng, et al. (2000). "Induction ofThl response by
`dendritic cells pulsed with autologous melanoma apoptotic bodies."
`Anticancer Res 20(3A): 1329-36.
`
`(Continued)
`
`Primary Examiner-Michail A Belyavskyi
`(74) Attorney, Agent, or Firm-Z. Peter Sawicki; Westman,
`Champlin & Kelly, P.A.
`
`(57)
`
`ABSTRACT
`
`Ex-vivo prepared T-cells are harvested from cell culture con(cid:173)
`ditions and formulated in medium suitable for infusion. The
`formulation is made by labeling the cells with one or more
`agents which have reactivity for T-cell surface moieties
`capable of delivery activation signals upon cross-linking and
`mixing the labeled cells with biodegradable nanospheres or
`microspheres coated with a material capable of cross-linking
`the agents attached to the T-cell surface moieties. Alterna(cid:173)
`tively, the formulation may be made by mixing a population
`of T-cells with biodegradable nanospheres or microspheres
`coated with a first material and one or more second materials.
`The first material binds the second material and the second
`material has reactivity for surface moieties on the T-cells and
`the interaction of the second materials with the T-cells causes
`the activation of the T-cells. In either method, the mixture of
`T-cells and biodegradable spheres are suspended in a medium
`suitable for infusion, and the mixture is packaged in a con(cid:173)
`tainer.
`
`3 Claims, No Drawings
`
`UPenn Ex. 2042
`Miltenyi v. UPenn
`IPR2022-00855
`
`

`

`US 7,402,431 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`tumors:
`solid
`transplantation."
`
`Chen, Q. et al. (1994). "Production of IL-10 by Melanoma Cells:
`Examination of its Role in Immunosuppression Mediated by Mela(cid:173)
`noma." Int. J Cancer, vol. 56, No. 5: pp. 755-760.
`Childs, R. et al. (2002). "Nonmyeloablative Stem Cell Transplanta(cid:173)
`tion for Solid Tumors: Expanding the Application of Allogenic
`Immunotherapy." Seminars in Hematology, vol. 39, No. 1: pp. 63-71.
`Childs, R. et al. (2000). "Regression of metastatic renal-cell carci(cid:173)
`noma after nonmyeloablative allogenic peripheral-blood stem-cell
`transplantation," The New England Journal of Medicine, vol. 343,
`No.11: pp. 750-758.
`Childs, R. W. (2000). "Nonmyeloablative allogeneic peripheral
`blood stem-cell transplantation as immunotherapy for malignant dis(cid:173)
`eases." Cancer J6(3): 179-87.
`Childs, R. W.
`(2002). "Immunotherapy for
`nonmyeloablative
`allogeneic
`stem
`cell
`MedGenMed 4(3): 13.
`Clerici, M. et al. (1993). "A TH1->TH2 switch is a critical step in
`theetiologyofHIV infection." Immunology Today, vol. 14, No. 3: pp.
`107-111.
`Cohen, P. A., L. Peng, et al. (2000). "CD4+ T cells in adoptive
`immunotherapy and the indirect mechanism of tumor rejection." Crit
`Rev Immunol 20(1): 17-56.
`Damle, N.K. et al. (1989). "Stimulation Via the CD3 and CD28
`Molecules Induces Responsiveness to IL-4 in CD4+CD29+CD45R(cid:173)
`MemoryT Lymphocytes." The Journal of Immunology, vol. 143, No.
`6: pp.1761-1767.
`Das, H., S. Imoto, et al. (2001 ). "Kinetic analysis of cytokine gene
`expression in patients with GVHD after donor lymphocyte infus(cid:173)
`tion." Bone Marrow Transplant 27(4): 373-80.
`Daubener, W. et al. (1995). "Establishment ofT-helper type 1- and
`T-helper type 2-like human Toxoplasma antigen-specific T-cell
`clones." Immunology, vol. 86, No. 1: pp. 79-84.
`Deeths, M. J. et al. (1999). "CDS+ T Cells Become Nonresponsive
`(Anergic) Following Activation in the Presence of Co stimulation."
`The Journal of Immunology, vol. 163, No. 1: pp. 102-110.
`De Vita, F., M. Orditura, et al. (2000). "Serum interleukin-10 is an
`independent prognostic factor in advanced solid tumors." Oneal Rep
`7(2): 357-61.
`de Waal Malefyt, R. et al. (1993). "Direct Effects ofIL-10 on Subsets
`of Human CD4+ T Cell Clones and Resting T Cells. Specific Inhibi(cid:173)
`tion of IL-2 Production and Proliferation." The Journal of Immunol(cid:173)
`ogy, vol. 150, No. 11: pp. 4754-4765.
`D'Orazio, T. J. et al. (1998). "A Novel Role for TGF-f:l and IL-10 in
`the Induction oflmmune Privilege." The Journal of Immunology, vol.
`160, No. 5: 2089-2098.
`Dudley, M. E. et al. (2002). "Cancer Regression andAutoimmunity in
`Patients After Clonal Repopulation with Antitumor Lymphocytes."
`Science, vol. 298, No. 5594: pp. 850-854.
`Egeter, 0. et al. (2000). "Eradication of Disseminated Lymphomas
`with CpG-DNA Activated T Helper 1 Cells from Nontransgenic
`Mice." Cancer Research, vol. 60, No. 6: 1515-1520.
`Eibl, B. et al. (1996). "Evidence for a Graft-Versus-Tumor Effect in
`a Patient Treated With Marrow Ablative Chemotherapy and
`Allogeneic Bone Marrow Transplantation for Breast Cancer." Blood,
`vol. 88, No. 4: pp. 1501-1508.
`Elsasser-Beile, U. et al. (1999). "Semiquantitative analysis of Thl
`and Th2 cytokine expression in CD3+, CD4+, and CDS+ renal-cell(cid:173)
`carcinoma-infiltrating lymphocytes." Cancer Immunol Immunother,
`vol. 48, No. 4: pp. 204-208.
`Emori, Y., H. Sasaki, et al. (1996). "Effect of Z-100, an
`immunomodulator extracted from human type tubercle bacilli, on the
`pulmonary metastases of Lewis lung carcinoma in attempt to regulate
`suppressor T cells and suppressor factor, IL-4." Biotherapy 9(4):
`249-56.
`Ertl, B., F. Heigl, et al. (2000). "Lectin-mediated bioadhesion: prepa(cid:173)
`ration, stability and caco-2 binding of wheat germ agglutinin(cid:173)
`functionalized Poly(D,L-lactic-co-glycolic acid)-microspheres." J
`Drug Targt 8(3): 173-84.
`Fan, X. G., W. E., Liu, et al. (1998). "Circulating Thl and Th2
`cytokines in patients with hepatitis C virus infection." Mediators
`Infiamm 7(4): 295-7.
`
`Finke, J. H., P. Rayman, et al. (1992). "Characterization of a human
`renal cell carcinoma specific cytotoxic CDS+ T cell line." J
`Immunother 11(1): 1-11.
`Finke, J. H., P. Rayman, et al. (1994). "Characterization oftumor(cid:173)
`infiltrating lymphocyte subsets from human renal cell carcinoma:
`specific reactivity defined by cytotoxicity, interferon-gamma secre(cid:173)
`tion, and proliferation." J Immunother Emphasis Tumor Immunol
`15(2): 91-104.
`Flanagan, D. L. et al. (1999). "Thl Cytokines and NK Cells Partici(cid:173)
`pate in the Development of Murine Syngeneic Graft-Versus-Host
`Disease." The Journal of Immunology, vol. 163, No. 3: pp. 1170-
`1177.
`Fowler, D. H., J. Breglio, et al. (1996). "Allospecific CD4+, Thl/Th2
`and CDS+, Tc l/Tc2 population in murine GVL: type I cells generate
`GVL and type II calls abrogate GVL." Biol Blood Marrow Transplant
`2(3): 118-25.
`Fowler, D. H. and R. E. Gress (2000). "Th2 and Tc2 cells in the
`regulation ofGVHD, GVL, and graft rejection: considerations for the
`allogeneic transplantation therapy ofleukemia and lymphoma." Leuk
`Lymphoma 38(3-4): 221-34.
`Frassoni, F., M. Labopin, et al. (1996). "Results of allogeneic bone
`marrow transplantation for acute leukemia have improved in Europe
`with time-a report of the acute leukemia working party of the
`European group for blood and marrow transplantation (EBMT)."
`Bone Marrow Transplant 17(1): 13-8.
`Freeman, G. J. et al. (2002). "Protect the killer: CTLs need defenses
`against the tumor." Nature Medicine, vol. 8, No. 8: pp. 787-789.
`Friess, H., H. G. Berger, et al. (1996). "Treatment of advanced pan(cid:173)
`creatic cancer with mistletoe: results of a pilot trial." Anticancer Res
`16(2): 915-20.
`Fujimoto, T. et al. (1997). "Streptococcal Preparation OK-432 is a
`Potent Inducer ofIL-12 and a T Helper Cell l Dominant State." The
`Journal of Immunology, vol. 158, No. 12: pp. 5619-5626.
`Fujisao, S. et al. (1998). "Thl/Th2 balance alteration in the clinical
`course of a patient with pure red cell aplasia and thymorna." British
`Journal of Haematology, vol. 103, No. 2: pp. 308-310.
`Gabrilovich, D. I. et al. (1996). "Dendritic Cells in Antitumor
`Immune Responses. II. Dendritic Cells Grown from Bone Marrow
`Precursors, but Not Mature DC from Tumor-Bearing Mice, Are
`Effective Antigen Carriers in the Therapy of Established Tumors."
`Cellular Immunology, vol. 170, No. 1: pp. 111-119.
`Gale, R. P. et al. (1984). "How Does Bone-Marrow Transplantation
`Cure Leukaemia?" The Lancet, vol. 2, No. 8393: pp. 28-30.
`Garlie, N.K., A.V. Lefever, et al. (1999). "T cells coactivated with
`immobilized anti-CD3 and anti-CD28 as potential immunotherapy
`for cancer." J Immunother 22(4): 336-45.
`Geppert, T.D. et al. (1988). "Activation ofT Lymphocytes by Immo(cid:173)
`bilized Monoclonal Antibodies to CD3, Regulatory Influences of
`Monoclonal Antibodies to Addition T Cell Surface Determinants." J
`Clin. Invest., vol. 81: pp. 1497-1505.
`Ghosh, P., K. L. Komschlies, et al. (1995). "Gradual loss ofT-helper
`1 populations in spleen of mice during progressive tumor growth." J
`Natl Cancer Inst 87(19): 1478-83.
`Gorelik, L., A. Prokhorova, et al. (1994). "Low-dose melphalan(cid:173)
`induced shift in the production of a Th2-type cytokine to a Thl-type
`cytokine in mice bearing a large MOPC 315 tumor." Cancer Immunol
`Immunother 39(2): 117-26.
`Grakoui, A. et al. ( 1999). "The Immunological Synapse: A Molecular
`Machine Controlling T Cell Activation." Science, vol. 285, No. 5425:
`pp. 221-227.
`Granucci, F. et al. (2001 ). "Transcriptional reprogranuning of
`dendritic cells by differentiation stimuli." Eur J Immunol, vol. 31, No.
`9, pp. 2539-2546.
`Grigg, A., P. Bardy, et al. (1999). "Fludarabine-based non(cid:173)
`myeloablative chemotherapy followed by infusion ofHLA-identical
`stem cells for relapsed leukaemia and lymphoma." Bone Marrow
`Transplant 23(2): 107-10.
`Grohmann, U., M. C. Fioretti, et al. (1998). "Dendritic cells,
`interleukin 12, and CD4+ lymphocytes in the initiation of class I-re(cid:173)
`stricted reactivity to a tumor/self peptide." Crit. Rev. Immunol 18( 1-
`2): 87-98.
`
`UPenn Ex. 2042
`Miltenyi v. UPenn
`IPR2022-00855
`
`

`

`US 7,402,431 B2
`Page 3
`
`Hara, I., H. Horta, et al. (1996). "Rejection of mouse renal cell
`carcinoma elicited by local secretion of interleukin-2." Jpn J Cancer
`Res 87(7): 724-9.
`Heine, G. et al. (2002). "A shift in the Th( 1 )/Th(2) ratio accompanies
`the clinical remission of systemic lupus erythematosus in patients
`with end-stage renal disease." Nephrology Dialysis Transplantation,
`vol. 17, No. 10: pp. 1790-1794.
`Heniford, B. T. et al. (1994). "Interleukin-8 Suppressed the Toxicity
`andAntitumor Effect oflnterleukin-2." Journal ofSurgical Research,
`vol. 56, No. 1: pp. 82-8.
`Herlyn, D. and B. Birebent (1999). "Advances in cancer vaccine
`development." Ann Med 31( 1 ): 66-78.
`Horiguchi, S. et al. (1999). "Primary Chemically Induced Tumors
`Induce Profound Immunosuppression Concomitant with Apoptosis
`and Alterations in Signal Transduction in T Cells and NK Cells."
`Cancer Research, vol. 59, No. 12: pp. 2950-2956.
`Inagawa, H., T. Nishizawa, et al. (1998). "Mechanisms by which
`chemotherapeutic agents augment the antitumor effects of tumor
`necrosis factor: involvement of the pattern shift of cytokines from
`Th2 to Thl in tumor lesions." Anticancer Res 18(5D): 3957-64.
`Ito, N. et al. (1999). "Lung Carcinoma: Analysis ofT Helper Type 1
`and 2 Cells and T Cytotoxic Type 1 and 2 Cells by Intracellular
`Cytokine Detection with Flow Cytometry." Cancer, vol. 85, No. 11:
`pp. 2359-2367.
`James, P. W. et al. ( 1999). "Aggregation of Lipid Rafts Accompanies
`Signaling Via the T Cell Antigen Receptor." The Journal of Cell
`Biology, vol. 147, No. 2: pp. 447-461.
`Jung, U. et al. (Nov. 2003). "CD3/CD28-costimulated Tl and T2
`subsets: differential in vivo allosensitization generates distinct GVT
`and GVHD effects." Blood, vol. 1, No. 9: pp. 3439-3446.
`Kadowaki, N. et al. (2002). "Natural Type 1 Interferon-Producing
`Cells as a Link Between Innate and Adaptive Immunity." Human
`Immunology, vol. 63, No. 12: pp. 1126-1132.
`Kai, S. and H. Hara (2003). "Allogeneic hematopoietic stem cells
`transplantation." Therap Apher Dia/7(3): 285-91.
`Kasakura, S. (1998). "[A role forT-helpertype 1 and type 2 cytokines
`in the pathogenesis of various human diseases]." Rinsho Byori 46(9):
`915-21.
`Kitahara, S., M. Ikeda, et al. (1996). "Inhibition of head and neck
`metastatic and/or recurrent cancer by local administration of multi(cid:173)
`cytokine inducer OK-432." J Laryngol Otol 110(5): 449-53.
`Knoefel, B., K. Nuske, et al. (1997). "Renal cell carcinomas produce
`IL-6, IL-10, IL-11, and TGF-beta 1 in primary cultures and modulate
`T lymphocyte blast transformation." J Interferon Cytokine Res 17(2):
`95-102.
`Kobayaski, M. et al. (1998). "A Pathogenic Role ofTh2 Cells and
`Their Cytokine Products on the Pulmonary Metastasis of Murine B 16
`Melanoma." The Journal of Immunology, vol. 160, No. 12: pp. 5869-
`5873.
`Kobayashi, M., R. B. Pollard, et al. (1997). "Inhibition of pulmonary
`metastasis by Z-100, an immunomodulatory lipid-arabinomannan
`extracted from Mycobacterium tuberculosis, in mice inoculated with
`Bl6 melanoma." Anticancer Drugs 8(2): 156-63.
`Lahn, M. et al. (1999). "Pro-Inflanunatory and T Cell Inhibitory
`Cytokines Are Secreted at High Levels in Tumor Cell Cultures of
`Human Renal Cell Carcinoma." European Urology, vol. 35, No. 1:
`pp. 70-80.
`Langenkamp, A. et al. (2000). "Kinetics of dendritic cell activation:
`impact on priming, THl, TH2 and nonpolarized T cells." Nature
`Immunology, vol. 1, No. 4: 311-316.
`Laux, I. et al. (2000). "Response Differences between Human
`CD4( +) and CDS(+) T-Cells during CD28 Co stimulation: Implica(cid:173)
`tions for Immune Cell-Based Therapies and Studies Related to the
`Expansion of Double-Positive T-Cells during Aging." Clinical Immu(cid:173)
`nology, vol. 96, No. 3: pp. 187-197.
`Le Bon, A. et al. (2002). "Links between innate and adaptive immu(cid:173)
`nity via type I interferon." Current Opinion Immunology, vol. 14, No.
`4. pp. 432-436.
`Lee, P. P. et al. (1997). "T Helper 2-Dominant Antilymphoma
`Immune Response Is Associated With Fatal Outcome." Blood, vol.
`90, No. 4: pp. 1611-1617.
`
`Levine, B.L. et al. (1997). "Effects ofCD28 Costimulation on Long(cid:173)
`Term Proliferation of CD4+ T Cells in the Absence of Exogenous
`Feeder Cells." The Journal of Immunology, vol. 159, No. 12: pp.
`5921-5930.
`Li, L. et al. ( 1998). "Cyclophosphamide Given After Active Specific
`Immunization Augments Antitumor Immunity by Modulation ofThl
`Commitment ofCD4+ T Cells." Journal of Surgical Oncology, vol.
`67, No. 4: pp. 221-227.
`Liebowitz, D.N. et al. ( 1998). "Costimulatory approaches to adoptive
`immunotherapy." Current Opinion Oncology, vol. 10, No. 6: pp.
`533-541.
`Lowes, M. A., G. A. Bishop, et al. (1997). "T helper 1 cytokine
`mRNA is increased in spontaneously regressing primary melano(cid:173)
`mas." J Invest Dermatol 108(6): 914-9.
`Ludviksson, B. R. et al. (2000). "The effect ofTGF-f:ll on immune
`responses of naive versus memory CD4+ Thl/Th2 T cells." Eur J
`Immunol, vol. 30, No. 7: pp. 2101-2111.
`Lum, L.G. et al (2001 ). "Immune modulation in cancer patients after
`of
`anti-CD3/anti-CD28-costimulated
`adoptive
`transfer
`T-cells-phase I clinical trial." Journal of Immunotherapy, vol. 24,
`No. 5: pp. 408-419.
`Ma, J. et al. ( 1998). "Use of encapsulated single chain antibodies for
`induction of anti-idiotypic humoral and cellular immune responses."
`Journal of Pharmaceutical Sciences, vol. 87, No. 11: pp. 1375-1378.
`Maeurer, M. J., D. M. Martin, et al. (1995). "Host immune response
`in renal cell cancer: interleukin-4 (IL-4) and IL-10 mRNA are fre(cid:173)
`quently detected in freshly collected tumor-infiltrating lympho(cid:173)
`cytes." Cancer Immunol Immunother 41(2): 111-21.
`Maus, M. V. et al. (2002). "Ex vivo expansion of polyclonal and
`antigen-specific cytotoxic T lymphocytes by artificial APCs express(cid:173)
`ing ligands for the T-cell receptor, CD28 and 4-IBB." Nature
`Biotechnology, vol. 20, No. 2: pp. 143-148.
`Menetrier-Caux, C. et al. ( 1999). "Renal cell carcinoma induces
`interleukin 10 and prostaglandin E2 production by monocytes." Brit(cid:173)
`ish Journal of Cancer, vol. 79, No. 1: pp. 119-130.
`Moran, M. et al. (1998). "Engagement of GPI-Linked CD48 Con(cid:173)
`tributes to TCR Signals and Cytoskeletal Reorganization: A Role for
`Lipid Rafts in T Cell Activation." Immunity, vol. 9, No. 6: pp. 787-
`796.
`(2003). "Surface modification of PLGA
`Muller, M. et al.
`microspheres." Journal of Biomedic Material Research, vol.
`66A,No. 1: pp. 55-61.
`Nabioullin, R. et al. (1994). "Interleukin-10 is a potent inhibitor of
`tumor cytotoxicity by human monocytes and alveolar macrophages."
`Journal of Leukocyte Biology, vol. 55, No. 4: pp. 437-442.
`Nakagomi, H. et al. (1995). "Lack oflnterleukin-2 (IL-2) Expression
`and Selective Expression of IL-10 mRNA in Human Renal Cell
`Carcinoma." Int. Journal of Cancer, vol. 63, No. 3: pp. 366-371.
`Nishimura, T. et al. (2000). "The critical role ofThl-dominant immu(cid:173)
`nity in tumor immunology." Cancer Chemother Pharmacol, vol. 46
`(Suppl): S52-S61.
`Nitta, T., M. Hishii, et al. (1994). "Selective expression of
`interleukin-10 gene within glioblastoma multiforme." Brain Res
`649(1-2): 122-8.
`O'Donnell P.B. et al. (1997). "Preparation of microspheres by the
`solvent evaporation technique." Advanced Drug Delivery Reviews,
`vol. 28, No. 1: pp. 25-42.
`Oka, H. et al. (1999). "An immunomodulatory arabinomannan
`extracted from Mycobacterium tuberculosis, Z-100, restores the bal(cid:173)
`ance ofThl/Th2 cell responses in tumor bearing mice." Immunology
`Letters, vol. 70, No. 2: pp. 109-117.
`Okamoto, T. et al. (1997). "Local Injection ofOK432 Can Augment
`the THl-Type T-Cell Response in Tumor-Draining Lymph Node
`Cells and Increase Their Immunotherapeutical Potential." Interna(cid:173)
`tional Journal of Cancer, vol. 70, No. 5: pp. 598-605.
`Okutomi, T., Y. Kato, et al. (2000). "[Clinical effects of adjuvant
`therapy using Z-100 (Ancer 20 injection) for oral cancer-prevention
`of stomatitis and hematopoietic impairment]." Gan To Kagaku Ryoho
`27(1): 65-71.
`Onishi, T. et al. (1999). "An assessment of the immunological envi(cid:173)
`ronment based on intratumoral cytokine production in renal cell
`carcinoma." BJU International, vol. 83, No. 4: pp. 488-492.
`
`UPenn Ex. 2042
`Miltenyi v. UPenn
`IPR2022-00855
`
`

`

`US 7,402,431 B2
`Page 4
`
`Raghupathy, R. (1997). "Thl-type immunity is incompatible with
`successful pregnancy." Immunology Today, vol. 18, No. 10: pp. 478-
`482.
`Raghupathy, R. et al. (1999). "Maternal Thl- and Th2-Type Reactiv(cid:173)
`ity to Placental Antigens in Normal Human Pregnancy and Unex(cid:173)
`plained Recurrent Spontaneous Abortions." Cellular Immunology,
`vol. 196, No. 2: pp. 122-130.
`Rondon, G., S. Giralt, et al. (1996). "Graft-versus leukemia effect
`after allogeneic bone marrow
`transplantation
`for chronic
`lymphocytic leukemia." Bone Marrow Transplant 18(3): 669-72.
`Rosenberg, S. A. (2001). "Progress in the development of
`immunotherapy for the treatment of patients with cancer." Journal of
`Internal Medicine, vol. 250, No. 6: pp. 462-475.
`Roussel, E. et al. (1996). "Predominance of a type 2 intratumoral
`immune response in fresh tumor-infiltrating lymphocytes from
`human gliomas." Clinical and Experimental Immunology, vol. 105,
`No. 2: pp. 344-352.
`Rubbi, C.P. et al. (1993). "Evidence of surface antigen detachment
`during incubation of cells with immunomagnetic beads." Journal of
`Immunology Methods, vol. 166, No. 2: pp. 233-241.
`Santin, A. D. et al. (2000). "Interleukin-10 Increases Thl Cytokine
`Production and Cytotoxic Potential In Human Papillomavirus-Spe(cid:173)
`cific CDS(+) Cytotoxic T Lymphocytes." Journal ofVirology, vol. 74,
`No. 10: pp. 4729-4737.
`Sato, M., S. Goto, et al. (1998). "Impaired production of Thl
`cytokines and increased frequency of Th2 subsets in PBMC from
`advanced cancer patients." Anticancer Res 18(5D): 3951-5.
`Saxton, M. L. et al. (1997). "Adoptive Transfer of Anti-CD3-Acti(cid:173)
`vated CD4+ T Cells Plus Cyclophosphamide and Liposome-Encap(cid:173)
`sulated Interleukin-2 Cure Murine MC-38 and 3LL Tumors and
`Establish Tumor-Specific Immunity." Blood, vol. 89, No. 7: pp. 2529-
`2536.
`Shibuya, T.Y. et al. (2000). "Anti-CD3/ Anti-CD28 Bead Stimulation
`Overcomes CD3 Unresponsiveness in Patients With Head and Neck
`Squamous Cell Carcinoma." Arch Otolaryngol Head Neck Surg, vol.
`126, No. 4: 473-479.
`Shinomiya, Y., M. Harada, et al. (1995). "Anti-metastatic activity
`induced by in vivo activation of purified protein derivative (PPD )(cid:173)
`recognizing Thl type CD4+ T Cells." Immunobiology 193(5): 439-
`55.
`Shurin, M. R., L. Lu, et al. (1999), "Thl/Th2 balance in cancer,
`transplantation and pregnancy." Springer Semin Immunopathol
`21(3): 339-59.
`Slavin, S. et al. (2001). "Non-myeloablative allogeneic Stem cell
`transplantation focusing on immunotherapy of life-threatening
`malignant and non-malignant diseases." Critical Reviews Oncology
`Hematology, vol. 39, No. 1-2: pp. 25-29.
`Slavin, S. et al. (1995). "Allogenic cell therapy for relapsed leukemia
`after bone marrow transplantation with donor peripheral blood lym(cid:173)
`phocytes." Experimental Hematology, vol. 23, No. 14: pp. 1553-
`1562.
`Slavin, S. et al. ( 1996). "Allogenic Cell Therapy With Donor Periph(cid:173)
`eral Blood Cells and Recombinant Human Interleukin-2 to Treat
`Leukemia Relapse After Allogenic Bone Marrow Transplantation."
`Blood, vol. 87, No. 6: pp. 2195-1204.
`Slavin, S. et al. (1996). "Allogenic Cell Therapy: The Treatment of
`Choice for All Hematologic Malignancies Relapsing Post BMT."
`Blood, vol. 87, No. 9: pp. 4011-4013.
`Slavin, S. et al. (2001 ). "Nonmyeloablative stem cell transplantation
`for the treatment of cancer and life-threatening nonmalignant disor(cid:173)
`ders: past accomplishments and future goals." Cancer Chemother.
`Pharmacol, vol. 48, (Suppl 1): pp. S79-S84.
`Slavin, S. et al. (1998). "Immunotherapy in conjunction with
`autologous and allogenic blood or marrow transplantation in
`lymphoma." Annals of Oncology, vol. 9 (Suppl 1): pp. S31-S39.
`Smith, D.R., S. L. Kunkel, et al. (1994). "Production ofinterleukin-
`10 by human bronchogenic carcinoma." Am J Pathol 145(1): 18-25.
`Smyth, M. J. et al. (2002). "New Aspects of Natural-Killer-Cell
`Surveillance and Therapy of Cancer." Nature Reviews Cancer, vol. 2,
`No. 11: pp. 850-861.
`
`Sredni, B. et al. (1995). "Bone Marrow-Sparing and Prevention of
`Alopecia by ASlO 1 in Non-Small-Cell Lung Cancer Patients Treated
`with Carboplatin and Etoposide." Journal of Clinical Oncology, vol.
`13, No. 9: pp. 2342-2353.
`Sredni, B. et al. (1996). "Predominance ofTHl Response in Tumor(cid:173)
`Bearing Mice and Cancer Patients Treated with ASlOl." National
`Journal of Cancer Institute, vol. 88, No. 18: pp. 1276-1284.
`Sredni, B., R. H. Xu, et al. (1996). "The protective role of the
`immunomodulator ASl0l against chemotherapy-induced alopecia
`studies on human and animal models." Int J Cancer 65(1): 97-103.
`Stein, G., W. Henn, et al. (1998). "Modulation of the cellular and
`humoral immune responses of tumor patients by mistletoe therapy."
`Eur J Med Res 3(4): 194-202.
`Stern, B. V. et al. (2002). "Vaccination with Tumor Peptide in CpG
`Adjuvant Protects Via IFN-Garnma-Dependent CD4 Cell Immunity."
`The Journal of Immunology, vol. 168, No. 12: pp. 6099-6105.
`Tabata, T. et al. (1999). "Th2 Subset Dominance Among Peripheral
`Blood T Lymphocytes in Patients with Digestive Cancers." American
`Journal of Surgery, vol. 177, No. 3: pp. 203-208.
`Taga, K. et al. (1993). "Human Interleukin-10 Can Directly Inhibit
`T-Cell Growth." Blood, vol. 81, No. 11: pp. 2964-2971.
`Takeuchi, T. et al. ( 1997). "Th2-like response and antitumor effect of
`anti-interleukin-4 mAb in mice bearing renal cell carcinoma." Can(cid:173)
`cer Immunol Immunother, vol. 43, No. 6: pp. 375-381.
`Tanaka, K., K. Kemmotsu, et al. (1998). "[Flow cytometric analysis
`of helper T cell subets (Thl and Th2) in healthy adults]." Rinsho
`Byori 46(12): 1247-51.
`Tanaka, J., M. Imamura, et al. (1997). "The important balance
`between cytokines derived from type 1 and type 2 helper T cells in the
`control of graft-versus-host disease." Bone Marrow Transplant
`19(6): 571-6.
`Tatsumi, T. et al. (2002). "Disease-associated bias in T helper type 1
`(Thl)/Th2 CD4(+) T cell responses against MAGE-6 in HLA(cid:173)
`DRB10401(+) patients with renal cell carcinoma or melanoma."
`Journal of Experimental Medicine, vol. 196, No. 5: pp. 619-628.
`Terao, H., M. Harada, et al. (1994). "Thl type CD4+ T cells may be
`a potent effector aginst poorly immunogenic syngeneic tumors."
`Biotherapy 8(2): 143-51.
`Tessmar, J. et al. (2003). "The use ofpoly(ethylene glycol)-block(cid:173)
`poly(lactic acid) derived copolymers for the rapid creation of
`biomimetic surfaces." Biomaterials, vol. 24, No. 24: pp. 4475-4486.
`Thanhauser, A., A. Bohle, et al. (1995). "The induction ofbacillus(cid:173)
`Calmette-Guerin-activated killer cells requires the presence of
`monocytes and T-helper type-1 cells." Cancer Immunol Immunother
`40(2): 103-8.
`Thomas, A. K. et al. (2002). "A Cell-Based Artificial Antigen-Pre(cid:173)
`senting Cell Coated with Anti-CD3 and CD28 Antibodies Enables
`Rapid Expansion and Long-Term Growth of CD4 T Lymphocytes."
`Clinical Immunology, vol. 105, No. 3: pp. 259-272.
`Thomas, E., R. Storb, et al. (1975). "Bone-marrow transplantation
`(first of two parts)." N Engl J Med 292(16): 832-43.
`Thomas, E. D., R. Storb, et al. ( 197 5). "Bone-marrow transplantation
`(second of two parts)." N Engl J Med 292(17): 895-902.
`Tilg, H. et al. (1994). "Interleukin-6 (IL-6) as an Anti-inflammatory
`Cytokine: Induction of Circulating IL-1 Receptor Antagonist and
`Soluble Tumor Necrosis Factor Receptorp55." Blood, vol. 83, No. 1:
`pp. 113-118.
`To, W. C. et al. (2000). "Therapeutic Efficacy of Thl and Th2
`L-selectin----CD4+ Tumor-ReactiveT Cells." Laryngoscopevol. 110,
`(10 Pt 1): pp. 1648-1654.
`Ueno, N. T., G. Rondon, et al. (1998). "Allogeneic peripheral-blood
`progenitor-cell transplantation for poor-risk patients with metastatic
`breast cancer." J Clin Oncol 16(3): 986-93.
`van Besien, K., P. Thall, et al. (1997). "Allogenic transplantation for
`recurrent or refractory non-Hodgkin's lymphoma with poor prognos(cid:173)
`tic
`features after conditioning with
`thiotepa, busulfan, and
`cyclophosphamide: experience in 44 consecutive patients." Biol
`Blood Marrow Transplant 3(3): 150-6.
`Voutsadakis, I.A. (2003). "NK cells in allogeneic bone marrow trans(cid:173)
`plantation." Cancer Immunol Immunother, vol. 52, No. 9: pp. 525-
`534.
`
`UPenn Ex. 2042
`Miltenyi v. UPenn
`IPR2022-00855
`
`

`

`US 7,402,431 B2
`Page 5
`
`Vowels, B. R. et al. ( 1994). "Th2 Cytokine mRNA Expression in Skin
`in Cutaneous T-Cell Lymphoma." The Journal of Investigative Der(cid:173)
`matology, vol. 103, No. 5: pp. 669-673.
`Wang, Q. et al. (1995). "Selective Cytokine Gene Expression in
`Renal Cell Carcinoma Tumor Cells and Tumor-Infiltrating Lympho(cid:173)
`cytes." International Journal of Cancer, vol. 61, No. 6: pp. 780-785.
`Weber, K., U. Mengs, et al. ( 1998). "Effects of a standardized mistle(cid:173)
`toe preparation on metastatic B 16 melanoma colonization in murine
`lungs." Arzneimittelforschung 48(5): 497-502.
`Weiden, P. L. et al. (1981). "Antileukemic Effect of Chronic Graft(cid:173)
`Versus-Host Disease: Contribution to Improved Survival After
`Allogenic Marrow Transplantation." New England Journal of Medi(cid:173)
`cine, vol. 304 No. 25: pp. 1529-1533.
`Whitemore, M. et al. (1999). "LPD lipopolyplex initiates a potent
`cytokine response and inhibits tumor growth." Gene Therapy, vol. 6,
`No.11: pp. 1867-1875.
`Wong, B. R. et al. (1999). "Trance is a TNF family member that
`regulates dendritic cell and osteoclast function." Journal of
`Leukocyte Biology, vol. 65, No. 6: pp. 715-724.
`Woo, E. Y. et al. (2001). "Regulatory CD4(+)CD25(+) T Cells in
`Tumors from Patients with Early-Stage Non-Small Cell Lung Cancer
`
`and Late-Stage Ovarian Cancer." Cancer Research, vol. 61, No. 12:
`pp. 4766-4772.
`Woo, E. Y. et al. (2002). "Cutting edge: RegulatoryT Cells from Lung
`Cancer Patients Directly Inhibit Autologous T cell proliferation." J
`Immunol 168(9): 4272-6.
`Yarnarnura, M. (1992). "Defining protective responses to pathogens:
`cytokine profiles in leprosy lesions." Science 255(5040): 12.
`Yashiro-Ohtani, Y. e