A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint

Katherine M Bever, Dwayne L Thomas 2nd, Jiajia Zhang, Ernie A Diaz Rivera, Gary L Rosner, Qingfeng Zhu, Julie M Nauroth, Brian Christmas, Elizabeth D Thompson, Robert A Anders, Carol Judkins, Meizheng Liu, Elizabeth M Jaffee, Nita Ahuja, Lei Zheng, Nilofer S Azad, Katherine M Bever, Dwayne L Thomas 2nd, Jiajia Zhang, Ernie A Diaz Rivera, Gary L Rosner, Qingfeng Zhu, Julie M Nauroth, Brian Christmas, Elizabeth D Thompson, Robert A Anders, Carol Judkins, Meizheng Liu, Elizabeth M Jaffee, Nita Ahuja, Lei Zheng, Nilofer S Azad

Abstract

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3-4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.

Keywords: Colorectal cancer; Epigenetic therapy; GVAX; Immunotherapy.

Conflict of interest statement

Through a licensing agreement with Aduro Biotech, Dr. Jaffee and the Johns Hopkins University have the potential to receive royalties on the sale of GVAX. N. Ahuja has received grant funding from Cepheid and Astex and has served as consultant to Ethicon. She has licensed methylation biomarkers to Cepheid. No potential conflict of interest were disclosed by the other authors.

Figures

Fig. 1
Fig. 1
a Overall study design. b Treatment schema for Stage 1
Fig. 2
Fig. 2
Plot of CD45RO-positive cells per mm2 of tumor area as quantified by immunohistochemistry. Matched baseline and post-treatment measurements are connected by a line. In total, 17 samples were obtained at baseline and of those, 11 had matched post-treatment biopsies. 3 patients had 0 positive cells both at baseline and post-treatment, and 2 patients had 0 positive cells at baseline and no paired post-treatment biopsy. The two patients with change from absent infiltrate at baseline to mild to moderate infiltrate on treatment are indicated by a solid line. *Note: A very high pre-treatment measurement (125 CD45RO+ cells/mm2 at baseline) is excluded from this figure; the patient had no corresponding post-treatment sample

References

    1. Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596.
    1. Mlecnik B, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity. 2016;44(3):698–711. doi: 10.1016/j.immuni.2016.02.025.
    1. Pages F, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128–2139. doi: 10.1016/S0140-6736(18)30789-X.
    1. Suva ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339(6127):1567–1570. doi: 10.1126/science.1230184.
    1. Juo YY, et al. Epigenetic therapy for solid tumors: from bench science to clinical trials. Epigenomics. 2015;7(2):215–235. doi: 10.2217/epi.14.73.
    1. Azad NS, et al. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study. Oncotarget. 2017;8(21):35326–35338. doi: 10.18632/oncotarget.15108.
    1. Vansteenkiste J, et al. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs. 2008;26(5):483–488. doi: 10.1007/s10637-008-9131-6.
    1. van Groeningen CJ, et al. Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients. Cancer Res. 1986;46(9):4831–4836.
    1. Connolly RM, et al. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a phase II National Cancer Institute/Stand Up to Cancer Study. Clin Cancer Res. 2017;23(11):2691–2701. doi: 10.1158/1078-0432.CCR-16-1729.
    1. Li H, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5(3):587–598. doi: 10.18632/oncotarget.1782.
    1. Chiappinelli KB, et al. Combining epigenetic and immunotherapy to combat cancer. Cancer Res. 2016;76(7):1683–1689. doi: 10.1158/0008-5472.CAN-15-2125.
    1. Wrangle J, et al. Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget. 2013;4(11):2067–2079. doi: 10.18632/oncotarget.1542.
    1. Heninger E, et al. Inducible expression of cancer-testis antigens in human prostate cancer. Oncotarget. 2016;7(51):84359–84374. doi: 10.18632/oncotarget.12711.
    1. Woods DM, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma Res. 2013;23(5):341–348. doi: 10.1097/CMR.0b013e328364c0ed.
    1. Terranova-Barberio M, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017;8(69):114156–114172. doi: 10.18632/oncotarget.23169.
    1. Fonsatti E, et al. Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2'-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res. 2007;13(11):3333–3338. doi: 10.1158/1078-0432.CCR-06-3091.
    1. Sigalotti L, et al. Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2'-deoxycytidine. Cancer Res. 2004;64(24):9167–9171. doi: 10.1158/0008-5472.CAN-04-1442.
    1. Issa JJ, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099–1110. doi: 10.1016/S1470-2045(15)00038-8.
    1. Coral S, et al. Immunomodulatory activity of SGI-110, a 5-aza-2'-deoxycytidine-containing demethylating dinucleotide. Cancer Immunol Immunother. 2013;62(3):605–614. doi: 10.1007/s00262-012-1365-7.
    1. Laheru D, et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res. 2008;14(5):1455–1463. doi: 10.1158/1078-0432.CCR-07-0371.
    1. Zheng L, et al. A safety and feasibility study of an allogeneic colon cancer cell vaccine administered with a granulocyte-macrophage colony stimulating factor-producing bystander cell line in patients with metastatic colorectal cancer. Ann Surg Oncol. 2014;21(12):3931–3937. doi: 10.1245/s10434-014-3844-x.
    1. Kim, V.M., et al., Neoantigen-based EpiGVAX vaccine initiates antitumor immunity in colorectal cancer. JCI Insight, 2020. 5(9).
    1. Galon J, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–1964. doi: 10.1126/science.1129139.
    1. Kim Y, et al. Image analyzer-based assessment of tumor-infiltrating T cell subsets and their prognostic values in colorectal carcinomas. PLoS ONE. 2015;10(4):e0122183. doi: 10.1371/journal.pone.0122183.
    1. Nosho K, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222(4):350–366. doi: 10.1002/path.2774.
    1. Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Tsujikawa T, et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 2017;19(1):203–217. doi: 10.1016/j.celrep.2017.03.037.
    1. Sunshine JC, et al. PD-L1 expression in melanoma: a quantitative immunohistochemical antibody comparison. Clin Cancer Res. 2017;23(16):4938–4944. doi: 10.1158/1078-0432.CCR-16-1821.
    1. Yarchoan M, et al. A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer. Cancer Med. 2020;9(4):1485–1494. doi: 10.1002/cam4.2763.
    1. Lipson EJ, 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;13:214. doi: 10.1186/s12967-015-0572-3.
    1. Serafini P, et al. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res. 2004;64(17):6337–6343. doi: 10.1158/0008-5472.CAN-04-0757.
    1. Tsujikawa, T., et al., Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. Clin Cancer Res, 2020.
    1. Hellmann, M., et al., Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO)) in NSCLC Patients Previously Treated with Anti-PD-(L)1 Therapy. Journal of Thoracic Oncology. 13(10): S330.
    1. Johnson, M.L., et al., Phase 2 trial of mocetinostat in combination with durvalumab in NSCLC patients with progression on prior checkpoint inhibitor therapy. SITC 2018 Abstract Book. Washington, D.C: SITC 2018. Online.
    1. Christmas BJ, et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res. 2018;6(12):1561–1577. doi: 10.1158/2326-6066.CIR-18-0070.
    1. Cao Q, et al. Inhibiting DNA Methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology. 2014;155(12):4925–4938. doi: 10.1210/en.2014-1595.
    1. Thangavel J, et al. Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury. J Cell Sci. 2015;128(16):3094–3105. doi: 10.1242/jcs.170258.
    1. de Groot AE, Pienta KJ. Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget. 2018;9(29):20908–20927. doi: 10.18632/oncotarget.24556.
    1. Topper MJ, et al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2020;17(2):75–90. doi: 10.1038/s41571-019-0266-5.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere