Regression of Breast Cancer Metastases Following Treatment with
Irradiated SV-BR-1-GM, a GM-CSF Overexpressing Breast Cancer Cell
Line: Intellectual Property and Immune Markers of Response

Charles   L.   Wiseman; Alexander      Kharazi; Vivekananda   G.   Sunkari; Jacqueline   L.   Galeas; Vito      Dozio; Hind      Hashwah; Eva      Macúchová; William   V.   Williams; Markus   D.   Lacher

doi:10.2174/1574892817666220518123331

Abstract

Background: SV-BR-1-GM, derived from a patient with grade 2 (moderately differentiated) breast cancer, is a GM-CSF-secreting breast cancer cell line with properties of antigen-presenting cells. SV-BR-1-GM and next-generation versions are covered by several pending and granted patents.

Methods: We report findings from an open-label phase I, single-arm pilot study with irradiated SV-BR-1-GM cells in 3 breast and 1 ovarian cancer subjects. Inoculations were preceded by lowdose intravenous cyclophosphamide and followed by interferon-alpha2b injections into the SVBR- 1-GM inoculation sites. We assessed both cellular and humoral immune responses, and measured expression levels of SV-BR-1-GM HLA alleles.

Results: Treatment was generally safe and well tolerated. Immune responses were elicited universally. Overall survival was more than 33 months for three of the four patients. As previously reported, one patient had prompt regression of metastases in lung, breast, and soft tissue. Following cessation of treatment, the patient relapsed widely, including in the brain. Upon retreatment, rapid tumor response was again seen, including complete regression of brain metastases. Consistent with a role of Class II HLA in contributing to SV-BR-1-GM’s mechanism of action, this patient allele-matched SV-BR-1-GM at the HLA-DRB1 and HLA-DRB3 loci. We are in the process of developing next-generation SV-BR-1-GM, expressing patient-specific HLAs. Patent applications were filed in various jurisdictions. Thus far, one is granted, in Japan.

Conclusion: A whole-cell immunotherapy regimen with SV-BR-1-GM cells induced regression of metastatic breast cancer. We develop intellectual property based on SV-BR-1-GM’s predicted mechanism of action to develop additional whole-cell immunotherapies for cancer patients.

Keywords: SV-BR-1-GM, whole-cell immunotherapy, therapeutic cancer vaccine, hla, breast cancer, WO2017147600A1.

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[1]
Santegoets SJ, Stam AG, Lougheed SM, et al. Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab. J Immunother Cancer  2014; 2(1): 31.
 [http://dx.doi.org/10.1186/s40425-014-0031-3] [PMID: 26196012]

[2]
Chen G, Gupta R, Petrik S, et al. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res  2014; 2(10): 949-61.
 [http://dx.doi.org/10.1158/2326-6066.CIR-14-0058] [PMID: 25116755]

[3]
Creelan BC, Antonia S, Noyes D, et al. Phase II trial of a GM-CSF-producing and CD40L-expressing bystander cell line combined with an allogeneic tumor cell-based vaccine for refractory lung adenocarcinoma. J Immunother  2013; 36(8): 442-50.
 [http://dx.doi.org/10.1097/CJI.0b013e3182a80237] [PMID: 23994887]

[4]
Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol  2015; 33(12): 1325-33.
 [http://dx.doi.org/10.1200/JCO.2014.57.4244] [PMID: 25584002]

[5]
Lipson EJ, Sharfman WH, Chen S, et al. Safety and immunologic correlates of melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J Transl Med  2015; 13(1): 214.
 [http://dx.doi.org/10.1186/s12967-015-0572-3] [PMID: 26143264]

[6]
Tsioulias GJ, Gupta RK, Tisman G, et al. Serum TA90 antigen-antibody complex as a surrogate marker for the efficacy of a polyvalent allogeneic whole-cell vaccine (CancerVax) in melanoma. Ann Surg Oncol  2001; 8(3): 198-203.
 [http://dx.doi.org/10.1007/s10434-001-0198-y] [PMID: 11314934]

[7]
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: Moving beyond current vaccines. Nat Med  2004; 10(9): 909-15.
 [http://dx.doi.org/10.1038/nm1100] [PMID: 15340416]

[8]
Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: The first FDA-approved therapeutic cancer vaccine. Clin Cancer Res  2011; 17(11): 3520-6.
 [http://dx.doi.org/10.1158/1078-0432.CCR-10-3126] [PMID: 21471425]

[9]
Ko BK, Kawano K, Murray JL, et al. Clinical studies of vaccines targeting breast cancer. Clin Cancer Res  2003; 9(9): 3222-34.
 [PMID: 12960107]

[10]
Solinas C, Aiello M, Migliori E, Willard-Gallo K, Emens LA. Breast cancer vaccines: Heeding the lessons of the past to guide a path forward. Cancer Treat Rev  2020; 84: 101947.
 [http://dx.doi.org/10.1016/j.ctrv.2019.101947] [PMID: 31926403]

[11]
Sobol RE. The rationale for prophylactic cancer vaccines and need for a paradigm shift. Cancer Gene Ther  2006; 13(8): 725-31.
 [http://dx.doi.org/10.1038/sj.cgt.7700950] [PMID: 16543919]

[12]
Cheever MA, Chen W. Therapy with cultured T cells: Principles revisited. Immunol Rev  1997; 157(1): 177-94.
 [http://dx.doi.org/10.1111/j.1600-065X.1997.tb00982.x] [PMID: 9255630]

[13]
Elliott GT, McLeod RA, Perez J, Von Eschen KB. Interim results of a phase II multicenter clinical trial evaluating the activity of a therapeutic allogeneic melanoma vaccine (theraccine) in the treatment of disseminated malignant melanoma. Semin Surg Oncol  1993; 9(3): 264-72.
 [PMID: 8516615]

[14]
Mordoh J, Kairiyama C, Bover L, Solarolo E. Allogeneic cells vaccine increases disease-free survival in stage III melanoma patients. A non randomized phase II study. Medicina (B Aires)  1997; 57(4): 421-7.
 [PMID: 9674264]

[15]
Nemunaitis J, Jahan T, Ross H, et al. Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer. Cancer Gene Ther  2006; 13(6): 555-62.
 [http://dx.doi.org/10.1038/sj.cgt.7700922] [PMID: 16410826]

[16]
Vaishampayan U, Abrams J, Darrah D, Jones V, Mitchell MS. Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clin Cancer Res  2002; 8(12): 3696-701.
 [PMID: 12473578]

[17]
Mackiewicz A, Mackiewicz J, Wysocki PJ, et al. Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection. Expert Opin Investig Drugs  2012; 21(6): 773-83.
 [http://dx.doi.org/10.1517/13543784.2012.684753] [PMID: 22577889]

[18]
Hardacre JM, Mulcahy M, Small W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: A phase 2 study. J Gastrointest Surg  2013; 17(1): 94-100.
 [http://dx.doi.org/10.1007/s11605-012-2064-6] [PMID: 23229886]

[19]
Mackiewicz J, Karczewska-Dzionk A, Laciak M, et al. Whole cell therapeutic vaccine modified with hyper-IL6 for combinational treatment of nonresected advanced melanoma. Medicine (Baltimore)  2015; 94(21): e853.
 [http://dx.doi.org/10.1097/MD.0000000000000853] [PMID: 26020391]

[20]
Giaccone G, Bazhenova LA, Nemunaitis J, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer  2015; 51(16): 2321-9.
 [http://dx.doi.org/10.1016/j.ejca.2015.07.035] [PMID: 26283035]

[21]
Lacher MD, Bauer G, Fury B, et al. SV-BR-1-GM, a clinically effective GM-CSF-secreting breast cancer cell line, expresses an immune signature and directly activates CD4+ T lymphocytes. Front Immunol  2018; 9: 776.
 [http://dx.doi.org/10.3389/fimmu.2018.00776] [PMID: 29867922]

[22]
Lacher MD, Wagner JP, Wiseman CL, Williams WV. Whole-cell cancer vaccines and methods for selection thereof. W.O. Patent 2017147600A1, 2017.

[23]
Eisenbach L, Feldman M. Double transfectants of MHC genes as cellular vaccines for immunoprevention of tumor metastasis. E.P. Patent 0569678A2, 1993.

[24]
Eisenbach L, Feldman M. Double transfectants of the MHC genes as cellular vaccines for immuno prevention of tumor metastasis. U.S. Patent 5750102A, 1998.

[25]
Ostrand-Rosenberg S, Baskar S, Glimcher LH, Freeman GJ, Nadler LM. Tumor cells with increased immunogenicity and uses therefor. U.S. Patent 6149905A, 2000.

[26]
Podack E. Tumor vaccine. U.S. Patent 20100119537A1, 2010.

[27]
Ostrand-Rosenberg S, Bosch JJ, Ksander BR. Tumor cells from immune privileged sites as base cells for cell-based cancer vaccines. U.S. Patent 7807186B2, 2010.

[28]
Tamar Peretz T, Lotem M, Machlenkin A, et al. Allogeneic tumor cell vaccination. W.O. Patent 2012156969A1, 2012.

[29]
Wiseman C, Kharazi A. Breast cancer cell lines and uses thereof. U.S. Patent 7674456B2, 2010.

[30]
Wiseman CL, Kharazi A. Objective clinical regression of metastatic breast cancer in disparate sites after use of whole-cell vaccine genetically modified to release sargramostim. Breast J  2006; 12(5): 475-80.
 [http://dx.doi.org/10.1111/j.1075-122X.2006.00319.x] [PMID: 16958969]

[31]
Lacher MD, Wagner JP, Wiseman CL, Williams WV. Whole-cell cancer vaccines and methods for selection thereof. E.P. Patent 3419657A4, 2019.

[32]
Lacher MD, Wagner JP, Wiseman CL, Williams WV. Whole-cell cancer vaccines and methods for selection thereof. J.P. Patent 6901505B2, 2021.

[33]
Wiseman CL, Kharazi A, Phase I. Study with SV-BR-1 breast cancer cell line vaccine and GM-CSF: Clinical experience in 14 patients. Open Breast Cancer J  2010; 2(1): 4-11.
 [http://dx.doi.org/10.2174/1876817201002010004]

[34]
Bruderer R, Bernhardt OM, Gandhi T, et al. Optimization of experimental parameters in data-independent mass spectrometry significantly increases depth and reproducibility of results. Mol Cell Proteomics  2017; 16(12): 2296-309.
 [http://dx.doi.org/10.1074/mcp.RA117.000314] [PMID: 29070702]

[35]
Scheltema RA, Hauschild JP, Lange O, et al. The Q exactive HF, a benchtop mass spectrometer with a pre-filter, high-performance quadrupole and an ultra-high-field orbitrap analyzer. Mol Cell Proteomics  2014; 13(12): 3698-708.
 [http://dx.doi.org/10.1074/mcp.M114.043489] [PMID: 25360005]

[36]
Bray NL, Pimentel H, Melsted P, Pachter L. Erratum: Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol  2016; 34(8): 888.
 [http://dx.doi.org/10.1038/nbt0816-888d] [PMID: 27504780]

[37]
Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol  2016; 34(5): 525-7.
 [http://dx.doi.org/10.1038/nbt.3519] [PMID: 27043002]

[38]
Pimentel H, Bray NL, Puente S, Melsted P, Pachter L. Differential analysis of RNA-seq incorporating quantification uncertainty. Nat Methods  2017; 14(7): 687-90.
 [http://dx.doi.org/10.1038/nmeth.4324] [PMID: 28581496]

[39]
Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc  2009; 4(8): 1184-91.
 [http://dx.doi.org/10.1038/nprot.2009.97] [PMID: 19617889]

[40]
Bush SJ, McCulloch MEB, Summers KM, Hume DA, Clark EL. Integration of quantitated expression estimates from polyA-selected and rRNA-depleted RNA-seq libraries. BMC Bioinformatics  2017; 18(1): 301.
 [http://dx.doi.org/10.1186/s12859-017-1714-9] [PMID: 28610557]

[41]
Hruz T, Laule O, Szabo G, et al. Genevestigator v3: A reference expression database for the meta-analysis of transcriptomes. Adv Bioinforma  2008; 2008: 420747.
 [http://dx.doi.org/10.1155/2008/420747] [PMID: 19956698]

[42]
Wang S, Yan R, Wang B, et al. Prediction of co-expression genes and integrative analysis of gene microarray and proteomics profile of Keshan disease. Sci Rep  2018; 8(1): 231.
 [http://dx.doi.org/10.1038/s41598-017-18599-x] [PMID: 29321553]

[43]
Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/HLA database. Nucleic Acids Res  2020; 48(D1): D948-55.
 [PMID: 31667505]

[44]
Arimilli S, Cardoso C, Mukku P, Baichwal V, Nag B. Refolding and reconstitution of functionally active complexes of human leukocyte antigen DR2 and myelin basic protein peptide from recombinant alpha and beta polypeptide chains. J Biol Chem  1995; 270(2): 971-7.
 [http://dx.doi.org/10.1074/jbc.270.2.971] [PMID: 7529765]

[45]
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology  1991; 19(5): 403-10.
 [http://dx.doi.org/10.1111/j.1365-2559.1991.tb00229.x] [PMID: 1757079]

[46]
Dai X, Cheng H, Bai Z, Li J. Breast cancer cell line classification and its relevance with breast tumor subtyping. J Cancer  2017; 8(16): 3131-41.
 [http://dx.doi.org/10.7150/jca.18457] [PMID: 29158785]

[47]
Parise CA, Caggiano V. Breast cancer survival defined by the ER/PR/HER2 subtypes and a surrogate classification according to tumor grade and immunohistochemical biomarkers. J Cancer Epidemiol  2014; 2014: 469251.
 [http://dx.doi.org/10.1155/2014/469251] [PMID: 24955090]

[48]
Godoy-Ortiz A, Sanchez-Muñoz A, Chica Parrado MR, et al. Deciphering HER2 breast cancer disease: Biological and clinical implications. Front Oncol  2019; 9: 1124.
 [http://dx.doi.org/10.3389/fonc.2019.01124] [PMID: 31737566]

[49]
Sabatier R, Finetti P, Guille A, et al. Claudin-low breast cancers: Clinical, pathological, molecular and prognostic characterization. Mol Cancer  2014; 13(1): 228.
 [http://dx.doi.org/10.1186/1476-4598-13-228] [PMID: 25277734]

[50]
Soliman H, Khalil F, Antonia S. PD-L1 expression is increased in a subset of basal type breast cancer cells. PLoS One  2014; 9(2): e88557.
 [http://dx.doi.org/10.1371/journal.pone.0088557] [PMID: 24551119]

[51]
Yao F, Zhang C, Du W, Liu C, Xu Y. Identification of gene-expression signatures and protein markers for breast cancer grading and staging. PLoS One  2015; 10(9): e0138213.
 [http://dx.doi.org/10.1371/journal.pone.0138213] [PMID: 26375396]

[52]
Sotiriou C, Wirapati P, Loi S, et al. Gene expression profiling in breast cancer: Understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst  2006; 98(4): 262-72.
 [http://dx.doi.org/10.1093/jnci/djj052] [PMID: 16478745]

[53]
Neve RM, Chin K, Fridlyand J, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell  2006; 10(6): 515-27.
 [http://dx.doi.org/10.1016/j.ccr.2006.10.008] [PMID: 17157791]

[54]
Leinonen R, Sugawara H, Shumway M. International nucleotide sequence database collaboration. The sequence read archive. Nucleic Acids Res  2011; 39(Database issue): D19-21.
 [http://dx.doi.org/10.1093/nar/gkq1019] [PMID: 21062823]

[55]
Perez-Riverol Y, Csordas A, Bai J, et al. The PRIDE database and related tools and resources in 2019: Improving support for quantification data. Nucleic Acids Res  2019; 47(D1): D442-50.
 [http://dx.doi.org/10.1093/nar/gky1106] [PMID: 30395289]

[56]
Lopez R, Cowley A, Li W, McWilliam H. Using EMBL-EBI services via web interface and programmatically via web services. Curr Protoc Bioinformatics  2014; 48: 3121-50.
 [http://dx.doi.org/10.1002/0471250953.bi0312s48]

[57]
Park MH, Lee HJ, Bok J, et al. Korean BAC library construction and characterization of HLA-DRA, HLA-DRB3. J Biochem Mol Biol  2006; 39(4): 418-25.
 [PMID: 16889686]

[58]
Coquillard GJ, Tang TF, Steiner N, et al. DRB3 alleles with variations in the annealing sites of commonly used amplification primers. Tissue Antigens  2000; 55(6): 558-63.
 [http://dx.doi.org/10.1034/j.1399-0039.2000.550606.x] [PMID: 10902611]

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DOI https://dx.doi.org/10.2174/1574892817666220518123331	Print ISSN 1574-8928
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