Clinical trial NCT02661685: Safety Study of Adoptive Transfer of Autologous IKDC-like Cells
Official title: An Immunotherapy for Metastatic Cancer Patients by Adoptive Transfer of Autologous IKDC-like Cells - Phase 1 Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasm Metastasis
Keywords: Cancer immunotherapy
IFN-γ-producing killer dendritic cell-like cells
Natural killer cells
Lead sponsor: National Defense Medical Center, Taiwan
Sponsor class: OTHER
Collaborators: name: Ministry of Science and Technology, Taiwan
name: Academia Sinica, Taiwan
First posted: 2016-01-22
Enrollment: 6
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 3+3 statistics model
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety of adoptive transferring autologous IKDC-like cells

Detailed description: Cancer immunosurveillance in mice and human protects the host from outgrowth of tumor cells. This may establish a sufficient rationale for cancer immunotherapy that aims to control or eradicate tumor by an induction of effective anti-tumor immunity. The interest in developing cancer immunotherapy has intensified by the recent trials results showing durable responses in approximately 20% of patients who received various kinds of immunotherapy including adoptive transfer of tumor-specific T cells, cancer vaccines, and T cell response checkpoint blockade inhibition. Discoveries to date, natural killer (NK) cell function positively associates with reduction of cancer risk and with better survival of gastrointestinal stromal tumor patients. Interferon-producing killer dendritic cells (IKDCs) are a subpopulation of NK cells discovered in the mouse spleen, which can lyse tumor cells and acquire antigen presentation cell (APC) activity. We found putative IKDCs in human peripheral blood mononuclear cells (PBMCs); meanwhile, we also developed a method to expand IKDC-like cells from murine bone marrow and human PBMC ex vivo. The expanded human IKDC-like cells are cytotoxic toward several human leukemia cell lines and are capable to activate allogeneic T cells. For the in vivo anti-tumor activity, we found that two transfers of syngeneic murine IKDC-like cells reduced tumor burden in B16/OVA and B16/F10 melanoma and Lewis lung carcinoma models, and enhanced interferon (IFN)-γ production by the splenocytes of the tumor-bearing mice. Moreover, six transfers of IKDC-like cell significantly prolonged the survival of mice bearing B16/F10 melanoma. Based on these preclinical results, we hypothesize anti-tumor activity of human IKDC-like cells. We thus propose a phase 1 clinical trial to assess the safety of autologous IKDC-like cell therapy in metastatic cancer patients for determination of the maximum tolerated dose, and to monitor the immune parameters in patients before and after the IKDC-like cell transfer to investigate the therapeutic mechanism and biomarkers.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed metastatic/recurrent non-hematological cancer, stage IV at study entry.
* Age: 21-75 years.
* ECOG performance status 0-1.
* Patients must have at least one measurable lesion.
* Patients' disease must have failed at least one-line of standard chemotherapy/targeted therapy or other treatment in the metastatic setting.
* Patients' estimated life expectancy is more than 3 months.
* Patients who refuse chemotherapy, or who are physiologically unsuitable for chemotherapy or any other standard therapy per investigator's discretion will be considered eligible for this trial.
* Patients must have adequate bone marrow function, defined as WBC ≥ 3500/mm3, neutrophil ≥ 1500/mm3, lymphocyte ≥ 1,000/mm3, and platelet ≥ 100,000/mm3.
* Patients must have adequate liver and renal function, defined as serum alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 times normal, bilirubin ≤ 1.5 times normal range, and creatinine ≤ 1.5 times upper normal limit.
* All patients should have documentation of negative result of penicillin test.
* Women or men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
* All patients must be informed of the investigational nature of this study and must sign and give written informed consent.

Exclusion Criteria:

* Subjects with metastatic cancer in disease progression (expected survival time \< 3 months).
* Subjects who have had chemotherapy less than 4 weeks before the start of trial.
* Subjects who received IFN-γ or GM-CSF less than 4 weeks before the start of trial.
* Subjects who are HIV, HBV, or HCV positive.
* Patients who have central nervous system metastasis except for those whose CNS disease have been treated with radiotherapy (Disease-free \> 6 months) and/or surgery and have been stable for at least two weeks.
* Patients who have active acute or chronic infection (at the discretion of the investigator).
* Pregnant or breast-nursing women.
* Patients who have active cardiac disease requiring therapy for failure, angina, arrhythmia, or infarction within the preceding 6 months (exception: any patient whose cardiac failure is compensated on medications).
* Subjects who have received corticosteroids or other immunosuppressive agents less than 4 weeks before starting trial.
* Subjects who have asthma and/or are on treatment for asthma.
* Subjects with history of autoimmune disease, such as lupus, multiple sclerosis, Ankylosing Spondylitis, Systemic Sclerosis.
* Subjects with a history of other systemic disease..
* History of neoplastic disease within the last 5 years except for carcinoma in situ of the cervix, superficial bladder cancer or basal/squamous cell carcinoma of the skin.
* Subjects who present with open wounds.

Primary outcomes:
measure: Evaluation of subject with Grade 3 or above adverse events that received autologous IKDC-like cells, graded according to NCI-CTCAE v4.03
timeFrame: Through study complete, an average about 1.5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
Study officials:
affiliation: Attending Physician
name: Ming-Shen Dai, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 2000 Feb 21;191(4):661-8. doi: 10.1084/jem.191.4.661.
citation: Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235-71. doi: 10.1146/annurev-immunol-031210-101324.
citation: Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity. 2013 Jul 25;39(1):11-26. doi: 10.1016/j.immuni.2013.07.008.
citation: Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012 Mar 15;12(4):298-306. doi: 10.1038/nrc3245.
citation: Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1-10. doi: 10.1016/j.immuni.2013.07.012.
citation: Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15.
citation: Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013 May;10(5):267-76. doi: 10.1038/nrclinonc.2013.46. Epub 2013 Apr 2.
citation: Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Adoptive cell transfer immunotherapy. Oncoimmunology. 2012 May 1;1(3):306-315. doi: 10.4161/onci.19549.
citation: Thanendrarajan S, Nowak M, Abken H, Schmidt-Wolf IG. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res. 2011 Sep;35(9):1136-42. doi: 10.1016/j.leukres.2011.05.005. Epub 2011 Jun 8.
citation: Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008 Apr;8(4):299-308. doi: 10.1038/nrc2355.
citation: Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000 Nov 25;356(9244):1795-9. doi: 10.1016/S0140-6736(00)03231-1.
citation: Menard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, Nonn C, Chaput N, Taieb J, Delahaye NF, Flament C, Emile JF, Le Cesne A, Zitvogel L. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009 Apr 15;69(8):3563-9. doi: 10.1158/0008-5472.CAN-08-3807. Epub 2009 Apr 7.
citation: Rusakiewicz S, Semeraro M, Sarabi M, Desbois M, Locher C, Mendez R, Vimond N, Concha A, Garrido F, Isambert N, Chaigneau L, Le Brun-Ly V, Dubreuil P, Cremer I, Caignard A, Poirier-Colame V, Chaba K, Flament C, Halama N, Jager D, Eggermont A, Bonvalot S, Commo F, Terrier P, Opolon P, Emile JF, Coindre JM, Kroemer G, Chaput N, Le Cesne A, Blay JY, Zitvogel L. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 2013 Jun 15;73(12):3499-510. doi: 10.1158/0008-5472.CAN-13-0371. Epub 2013 Apr 16.
citation: Duan X, Deng L, Chen X, Lu Y, Zhang Q, Zhang K, Hu Y, Zeng J, Sun W. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol. 2011 Jun;28(2):466-74. doi: 10.1007/s12032-010-9480-9. Epub 2010 Mar 31.
citation: McGilvray RW, Eagle RA, Watson NF, Al-Attar A, Ball G, Jafferji I, Trowsdale J, Durrant LG. NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin Cancer Res. 2009 Nov 15;15(22):6993-7002. doi: 10.1158/1078-0432.CCR-09-0991. Epub 2009 Oct 27.
citation: de Kruijf EM, Sajet A, van Nes JG, Putter H, Smit VT, Eagle RA, Jafferji I, Trowsdale J, Liefers GJ, van de Velde CJ, Kuppen PJ. NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study. BMC Cancer. 2012 Jan 18;12:24. doi: 10.1186/1471-2407-12-24.
citation: Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 2011 Sep;121(9):3609-22. doi: 10.1172/JCI45816. Epub 2011 Aug 15.
citation: Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M, Pequignot M, Casares N, Terme M, Flament C, Opolon P, Lecluse Y, Metivier D, Tomasello E, Vivier E, Ghiringhelli F, Martin F, Klatzmann D, Poynard T, Tursz T, Raposo G, Yagita H, Ryffel B, Kroemer G, Zitvogel L. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med. 2006 Feb;12(2):214-9. doi: 10.1038/nm1356. Epub 2006 Jan 29.
citation: Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M, Brockstedt D, Dubensky TW, Stins MF, Lanier LL, Pardoll DM, Housseau F. Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med. 2006 Feb;12(2):207-13. doi: 10.1038/nm1352. Epub 2006 Jan 29.
citation: Himoudi N, Yan M, Bouma G, Morgenstern D, Wallace R, Seddon B, Buddle J, Eddaoudi A, Howe SJ, Cooper N, Anderson J. Migratory and antigen presentation functions of IFN-producing killer dendritic cells. Cancer Res. 2009 Aug 15;69(16):6598-606. doi: 10.1158/0008-5472.CAN-09-0501. Epub 2009 Aug 4.
citation: Pletneva M, Fan H, Park JJ, Radojcic V, Jie C, Yu Y, Chan C, Redwood A, Pardoll D, Housseau F. IFN-producing killer dendritic cells are antigen-presenting cells endowed with T-cell cross-priming capacity. Cancer Res. 2009 Aug 15;69(16):6607-14. doi: 10.1158/0008-5472.CAN-09-0508.
citation: Terme M, Mignot G, Ullrich E, Bonmort M, Minard-Colin V, Jacquet A, Schultze JL, Kroemer G, Leclerc C, Chaput N, Zitvogel L. The dendritic cell-like functions of IFN-producing killer dendritic cells reside in the CD11b+ subset and are licensed by tumor cells. Cancer Res. 2009 Aug 15;69(16):6590-7. doi: 10.1158/0008-5472.CAN-08-4473.
citation: Chaudhry UI, Plitas G, Burt BM, Kingham TP, Raab JR, DeMatteo RP. NK dendritic cells expanded in IL-15 exhibit antitumor responses in vivo. J Immunol. 2007 Oct 1;179(7):4654-60. doi: 10.4049/jimmunol.179.7.4654.
citation: Himoudi N, Nabarro S, Buddle J, Eddaoudi A, Thrasher AJ, Anderson J. Bone marrow-derived IFN-producing killer dendritic cells account for the tumoricidal activity of unpulsed dendritic cells. J Immunol. 2008 Nov 1;181(9):6654-63. doi: 10.4049/jimmunol.181.9.6654.
citation: Liao N, Lee G, Chang C: Generation of murine and human interferon-producing killer cell-like cells with anti-tumor activity. . (patent pending) 2013.
citation: Lanier LL, Phillips JH, Hackett J Jr, Tutt M, Kumar V. Natural killer cells: definition of a cell type rather than a function. J Immunol. 1986 Nov 1;137(9):2735-9. No abstract available.
citation: Burt BM, Plitas G, Nguyen HM, Stableford JA, Bamboat ZM, Dematteo RP. Circulating HLA-DR(+) natural killer cells have potent lytic ability and weak antigen-presenting cell function. Hum Immunol. 2008 Aug;69(8):469-74. doi: 10.1016/j.humimm.2008.06.009. Epub 2008 Jul 18.
citation: Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008 Mar;22(3):659-61. doi: 10.1096/fj.07-9574LSF. Epub 2007 Oct 17.
citation: Krause SW, Gastpar R, Andreesen R, Gross C, Ullrich H, Thonigs G, Pfister K, Multhoff G. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial. Clin Cancer Res. 2004 Jun 1;10(11):3699-707. doi: 10.1158/1078-0432.CCR-03-0683.
citation: Ishikawa E, Tsuboi K, Saijo K, Harada H, Takano S, Nose T, Ohno T. Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res. 2004 May-Jun;24(3b):1861-71.
citation: Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011 Oct 1;17(19):6287-97. doi: 10.1158/1078-0432.CCR-11-1347. Epub 2011 Aug 15.
citation: Yang YJ, Park JC, Kim HK, Kang JH, Park SY. A trial of autologous ex vivo-expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced non-small cell lung cancer as second- or third-line treatment: phase IIa study. Anticancer Res. 2013 May;33(5):2115-22.
citation: Yamaguchi T, Bamba K, Kitayama A, Kuroiwa Y, Yoshimatsu K, Shimakawa T, Ogawa K, Sekine T, Shimizu N, Yamamoto K. Long-term intravenous administration of activated autologous lymphocytes for cancer patients does not induce antinuclear antibody and rheumatoid factor. Anticancer Res. 2004 Jul-Aug;24(4):2423-9.
citation: Delyon J, Mateus C, Lefeuvre D, Lanoy E, Zitvogel L, Chaput N, Roy S, Eggermont AM, Routier E, Robert C. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol. 2013 Jun;24(6):1697-703. doi: 10.1093/annonc/mdt027. Epub 2013 Feb 24.
citation: Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, Chapman PB, Schwartz GK, Allison JP, Wolchok JD. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010 Apr 1;116(7):1767-75. doi: 10.1002/cncr.24951.
citation: Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, Ku G, Troncoso P, Logothetis CJ, Allison JP, Sharma P. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010 May 15;16(10):2861-71. doi: 10.1158/1078-0432.CCR-10-0569. Epub 2010 May 11.
citation: Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.