First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors

Barry H Smith, Tapan Parikh, Zoe P Andrada, Thomas J Fahey, Nathaniel Berman, Madeline Wiles, Angelica Nazarian, Joanne Thomas, Anna Arreglado, Eugene Akahoho, David J Wolf, Daniel M Levine, Thomas S Parker, Lawrence S Gazda, Allyson J Ocean, Barry H Smith, Tapan Parikh, Zoe P Andrada, Thomas J Fahey, Nathaniel Berman, Madeline Wiles, Angelica Nazarian, Joanne Thomas, Anna Arreglado, Eugene Akahoho, David J Wolf, Daniel M Levine, Thomas S Parker, Lawrence S Gazda, Allyson J Ocean

Abstract

Purpose: Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective.

Methods: Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant.

Results: RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs.

Conclusion: The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

Keywords: cancer clinical trial; cancer system biology; cell-based therapeutics; colorectal cancer treatment; gastrointestinal cancer; solid tumors.

Figures

Figure 1
Figure 1
(A) OS after first implantation of RMB (all patients n = 31). (B) OS after first implantation of RMB by tumor marker response (colorectal cancer patients n = 8). Notes: (A) Number of patients at risk at each death is indicated. (B) Responder = at least a 20% decline from implant 1 baseline in either CA 19-9 or CEA. Number of patients at risk at each death is indicated. Wilcoxon test gives more weight to the earlier portion of the time frame.

References

    1. Smith BH, Gazda LS, Conn BL, et al. Three-dimensional culture of mouse renal carcinoma cells in agarose macrobeads selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. Cancer Res. 2011;71(3):716–724.
    1. Smith BH, Gazda LS, Conn BL, et al. Hydrophilic agarose macrobead cultures select for outgrowth of carcinoma cell populations that can restrict tumor growth. Cancer Res. 2011;71(3):725–735.
    1. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–655.
    1. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use ininternational clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–376.
    1. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, editor. Evaluation of Chemotherapeutic Agents. New York: Columbia University Press; 1949. pp. 191–205.
    1. Caceres G, Puskas JA, Magliocco AM. Circulating tumor cells: a window into tumor development and therapeutic effectiveness. Cancer Control. 2015;22(2):167–176.
    1. Mirrakhimov AE, Ali AM, Khan M, Barbaryan A. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6(2):5389.
    1. Vodopivec DM, Rubio JE, Fornoni A, Lenz O. An unusual presentation of tumor lysis syndrome in a patient with advanced gastric adenocarcinoma: case report and literature review. Case Rep Med. 2012;2012:468452.
    1. Tiram G, Segal E, Krivitsky A, et al. Identification of dormancy-associated MicroRNAs for the design of osteosarcoma-targeted dendritic polyglycerol nanopolyplexes. ACS Nano. 2016;10(2):2028–2045.
    1. Fujita Y, Yoshioka Y, Ochiya T. Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci. 2016;107(4):385–390.
    1. Welf ES, Driscoll MK, Dean KM, et al. Quantitative multiscale cell imaging in controlled 3D microenvironments. Dev Cell. 2016;36(4):462–475.
    1. Mlecnik B, Bindea G, Krilovsky A, et al. The tumor microenvironment and immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med. 2016;8(327):ra26.
    1. Park JI, Lee J, Kwon JL, et al. Scaffold-free coculture spheroids of human colonic adenocarcinoma cells and normal colonic fibroblasts promote tumorigenicity in nude mice. Transl Oncol. 2016;9(1):79–88.
    1. Kojima M, Ochiai A. Special cancer microenvironment in human colonic cancer: concept of cancer microenvironment formed by peritoneal invasion (CPMI) and implication of subperitoneal fibroblast in cancer progression. Pathol Int. 2016
    1. Siriwardana PN, Luong TV, Watkins J, et al. Biological and prognostic significance of the morphological types and vascular patterns in colorectal liver metastases (CRLM) Medicine. 2016;95(8):1–10.
    1. Zhang J, Zhu L, Fang J, Ge Z, Li X. LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1a activation. J Exp Clin Cancer Res. 2016;35(29):1–11.
    1. Bedognetti D, Hendrickx W, Ceccarelli M, Miller LD, Seliger B. Disentangling the relationship between tumor genetic programs and immune responsiveness. Curr Opin Immunol. 2016;39:150–158.
    1. Buldak RJ, Pilc-Gumula K, Buldak L, et al. Effects of ghrelin, leptin and melatonin on the levels of reactive oxygen species, antioxidant enzyme activity and viability of the HCT 116 human colorectal carcinoma cell line. Mol Med Rep. 2015;12(2):2275–2282.
    1. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164(6):1226–1232.
    1. Sarioglu AF, Aceto N, Kojic N, et al. A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods. 2015;12(7):685–691.
    1. Mittra I, Khare NK, Raghuram GV, et al. Circulating nucleic acids damge DNA of health cells by integrating into their genomes. J Biosci. 2015;40(1):91–111.
    1. Mittra I. Circulating nucleic acids: a new class of physiological mobile genetic elements. F1000Res. 2015;4:924.
    1. Wang SM, Sun ZQ, Li HY, Wang J, Liu QY. Temporal identification of dysregulated genes and pathways in clear cell renal cell carcinoma based on systematic tracking of disrupted modules. Comput Math Methods Med. 2015;2015:313740.
    1. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–892.
    2. Erratum. N Engl J Med. 2012;367(10):976.
    1. Ling S, Hu Z, Yang Z, et al. Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A. 2015;112(47):E6496–E6505.
    2. Erratum. Proc Natl Acad Sci U S A. 2016;113(5):E663.
    1. Knox SS. From ‘omics’ to complex disease: a systems biology approach to gene-environment interactions in cancer. Cancer Cell Int. 2010;10:11.
    1. Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J. Cancer: a systems biology disease. Biosystems. 2006;83(2–3):81–90.
    1. Menche J, Sharma A, Kitsak M, et al. Disease networks Uncovering disease-disease relationships through the incomplete interactome. Science. 2015;347(6224):1257601.
    1. Thiagalingam S. Systems Biology of Cancer Progression. Cambridge, UK: Cambridge University Press; 2015.
    1. Abercrombie M. Contact inhibition: the phenomenon and its biological implications. Natl Cancer Inst Monogr. 1967;26:249–277.
    1. Abercrombie M. Contact inhibition in tissue culture. In Vitro. 1970;6(2):128–142.
    1. Burger MM, Noonan KD. Restoration of normal growth by covering of agglutinin sites on tumor cell surface. Nature. 1970;228(5271):512–515.
    1. Seluanov A, Hine C, Azpurua J, et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci U S A. 2009;106(46):19352–19357.
    1. Roycroft A, Mayor R. Forcing contact inhibition of locomotion. Trends Cell Biol. 2015;25(7):373–375.
    1. Hernández-Sánchez M, Poch E, Guasch RM, et al. RhoE is required for contact inhibition and negatively regulates tumor initiation and progression. Oncotarget. 2015;6(19):17479–17490.
    1. Sharif GM, Schmidt MO, Yi C, et al. Cell growth density modulates cancer cell vascular invasion via Hippo pathway activity and CXCR2 signaling. Oncogene. 2015;34(48):5879–5889.
    1. Alkasalias T, Flaberg E, Kashuba V, et al. Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent. Proc Natl Acad Sci U S A. 2014;111(48):17188–17193.
    1. Knuchel S, Anderle P, Werfelli P, Diamantis E, Rüegg C. Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion. Oncotarget. 2015;6(16):14300–14317.
    1. Lin B, Yin T, Wu YI, Inoue T, Levchenko A. Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration. Nat Commun. 2015;6:6619.
    1. DeWys WD. Studies correlating the growth rate of a tumor and its metastases and providing evidence for tumor-related systemic growth-retarding factors. Cancer Res. 1972;32(2):374–379.
    1. Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res. 1989;49(8):1996–2001.
    1. Comen E, Norton L. Self-seeding in cancer. Recent Results Cancer Res. 2012;195:13–23.
    1. Speer JF, Petrosky VE, Retsky MW, Wardwell RH. A stochastic numerical model of breast cancer growth that simulates clinical data. Cancer Res. 1984;44(9):4124–4130.
    1. Prehn RT. The inhibition of tumor growth by tumor mass. Cancer Res. 1991;51(1):2–4.
    1. Schutte A, Udwadia F. New approach to the modeling of complex multibody dynamical systems. J Appl Mech. 2011;78(2):021018.
    1. Jain K, Yang H, Cai BR, et al. Retrievable, replaceable, macroencapsulated pancreatic islet xenografts. Long-term engraftment without immunosuppression. Transplantation. 1995;59(3):319–324.
    1. Jain K, Asina S, Yang H, et al. Glucose control and long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression. Transplantation. 1999;68(11):1693–1700.
    1. Magariños AM, Jain K, Blount ED, Reagan L, Smith BH, McEwen BS. Peritoneal implantation of macroencapsulated porcine pancreatic islets in diabetic rats ameliorates severe hyperglycemia and prevents retraction and simplification of hippocampal dendrites. Brain Res. 2001;902(2):282–287.
    1. Gazda LS, Adkins H, Bailie JA, et al. The use of pancreas biopsy scoring provides reliable porcine islet yields while encapsulation permits the determination of microbiological safety. Cell Transplant. 2005;14(7):427–439.
    1. Gazda LS, Vinerean HV, Laramore MA, et al. Encapsulation of porcine islets permits extended culture time and insulin independence in spontaneously diabetic BB rats. Cell Transplant. 2007;16(6):609–620.
    1. Martis PC, Laramore MA, Dudley A, Smith BH, Gazda LS. MEF2 plays a significant role in the tumor inhibitory effects of agarose encapsulated RENCA cells through the EGF receptor; AACR Annual Meeting; Philadelphia, PA. 2015. Abstract #1675.
    1. Schukur L, Geering B, Charpin-El Hamri G, Fussenegger M. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Sci Transl Med. 2015;7(318):318ra201.

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