Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma

Robert O Dillman, Andrew N Cornforth, Edward F McClay, Carol Depriest, Robert O Dillman, Andrew N Cornforth, Edward F McClay, Carol Depriest

Abstract

Aim: Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines.

Patients & methods: A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930).

Results: Toxicity was minimal. Median overall survival (OS) was 49.4 months; 5-year OS 46%. A 5-year OS was 72% for 18 recurrent stage 3 without measurable disease when treated and 53% for 30 stage 4 without measurable disease when treated. A total of 24 patients with measurable stage 4 when treated (median of four prior therapies) had an 18.5 months median OS and 46% 2-year OS.

Conclusion: This dendritic cell vaccine was associated with encouraging survival in all three clinical subsets. Clinicaltrial.gov NCT00436930 and NCT00948480.

Keywords: autologous tumor antigens; dendritic cells; melanoma; patient-specific therapy; therapeutic vaccine.

Conflict of interest statement

Financial & competing interests disclosure Manufacturing of vaccines and the conduct and monitoring of the clinical trials was financed by the Hoag Hospital Foundation and Hoag Hospital. This included financial support of the Hoag Cell Biology Laboratory, the clinical trials staff and RO Dillman. The recent analysis and preparation of this manuscript was supported by AIVITA Biomedical, Inc. RO Dillman is now the Chief Medical Officer for AIVITA Biomedical, Inc., and is an employee and has equity in that company. AN Cornforth is an employee and has equity in TCRR Therapeutics, Inc. RO Dillman was previously the holder of the INDs, and author and principle investigator for both clinical trials, which were conducted while he was medical director of the Hoag Cancer Center in Newport Beach, CA, USA. AN Cornforth was a scientist in the Hoag Cell Biology Laboratory until the fall of 2011. EF McClay and C Depriest have nothing to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. Overall survival for all 72…
Figure 1.. Overall survival for all 72 melanoma patients treated with autologous dendritic cell vaccines loaded with autologous tumor antigens and survival in a single arm Phase II trial (n = 54) and in a randomized Phase II trial (n = 18).
Figure 2.. Overall survival for melanoma patients…
Figure 2.. Overall survival for melanoma patients treated with autologous dendritic cell vaccines loaded with autologous tumor antigens whose stages of disease at the time of treatment were stage 3 (n = 18), stage 4 with nonmeasurable disease per RECIST (n = 30), or measurable (M) disease per RECIST (n = 24).
M: Measurable; NM: Not measurable.

References

    1. Atkins MB, Lotze MT, Dutcher JP. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17(7), 2105–2116 (1999).
    1. Kirkwood JM, Manola J, Ibrahim JG. et al. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin. Cancer Res. 10(5), 1670–1677 (2004).
    1. Dillman RO. Melanoma vaccines: trials and tribulations. Vaccine Dev. Ther. 3, 57–78 (2013).
    1. Morton DL, Mozzillo N, Thompson JF. et al. An international, randomized, Phase III trial of bacillus–Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J. Clin. Oncol. 25(Suppl. 18), 8508 (2007).
    1. Hodi FS, O’Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
    1. Lawson DH, Lee S, Zhao F. et al. Randomized, placebo-controlled, Phase III trial of yeast-derived granulocyte–macrophage colony–stimulating factor (GM–CSF) versus peptide vaccination versus GM–CSF plus peptide vaccination versus placebo in patients with no evidence of disease after complete surgical resection of locally advanced and/or stage IV melanoma: a trial of the Eastern Cooperative Oncology Group – American College of Radiology Imaging Network Cancer Research Group (E4697). J. Clin. Oncol. 33(34), 4066–4076 (2015).
    1. Kantoff PW, Higano CS, Shore ND. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363(5), 411–422 (2010).
    1. Andtbacka RH, Kaufman HL, Collichio F. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33(25), 2780–2788 (2015).
    1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 438(6230), 69–74 (2015).

    2. •• Excellent review summarizing establishing existence of patient-specific neoantigens and importance as targets for immunotherapy.

    1. Tran E, Robbins PF, Rosenberg SA. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18(3), 255–262 (2017).
    1. Hundal J, Miller CA, Griffith M. et al. Cancer immmunogenomics: computational neoantigens identification and vaccine design. Cold Spring Harb. Symp. Quant. Biol. 81, 105–111 (2016).
    1. Türeci Ö, Vormehr M, Diken M. et al. Targeting the heterogeneity of cancer with individualized neoepitope vaccines. Clin. Cancer Res. 22(8), 1885–1896 (2016).
    1. Dillman RO, Selvan SR, Schiltz PM. Patient-specific dendritic-cell vaccines for metastatic melanoma. N. Engl. J. Med. 355(11), 1179–1181 (2006).
    1. Dillman RO, Cornforth AN, Nistor GI. Dendritic cell vaccines for melanoma: past, present, and future. Melanoma Manag. 3(4), 267–283 (2016).

    2. • Review of dendritic cell vaccines in treatment of melanoma and emphasis on the importance of antigen source.

    1. Balan S, Finnigan J, Bhardwaj N. Dendritic cell strategies for eliciting mutation-derived tumor antigen responses in patients. Cancer J. 23(2), 131–137 (2017).
    1. Kreiter S, Vormehr M, van de Roemer N. et al. MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520(7549), 692–696 (2015).
    1. Carreno BM, Magrini V, Becker-Hapak M. et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348(6236), 803–808 (2015).
    1. Dillman RO, Cornforth AN, Nistor G. Cancer stem cell antigen-based vaccines: the preferred strategy for active specific immunotherapy of metastatic melanoma? Expert Opin. Biol. Ther. 13(5), 643–656 (2013).
    1. Dillman RO. Is there a role for therapeutic cancer vaccines in the age of checkpoint inhibitors? Hum. Vaccin. Immunother. 13(3), 528–532 (2017).
    1. Dillman RO. An update on the relevance of vaccine research for the treatment of metastatic melanoma. Melanoma Manage. 4(4), 203–215 (2017).

    2. •• Summary of rational and evidence for role of vaccines as an adjunct to checkpoint inhibition in patients with metastatic melanoma.

    1. Dranoff G, Jaffee E, Lazenby A. et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte–macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl Acad. Soc. USA 90(8), 3539–3543 (1993).
    1. Dillman RO, Wiemann M, Nayak SK. et al. Interferon-gamma or granulocyte–macrophage colony-stimulating factor administered as adjuvants with a vaccine of irradiated autologous tumor cells from short-term cell line cultures: a randomized Phase II trial of the Cancer Biotherapy Research Group. J. Immunother. 26(4), 367–373 (2003).
    1. Kaufman HL, Ruby CE, Hughes T, Slingluff CL Jr. Current status of granulocyte–macrophage colony-stimulating factor in the immunotherapy of melanoma. J. Immunother. Cancer. 2(1), 11 (2014).
    1. Spitler LE, Grossbard ML, Ernstoff MS. et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte–macrophage colony-stimulating factor. J. Clin. Oncol. 18(8), 1614–1621 (2000).
    1. Spitler LE, Weber RW, Allen RE. et al. Recombinant human granulocyte–macrophage colony-stimulating factor (GM–CSF, sargramostim) administered for 3 years as adjuvant therapy of stages II (T4), III, and IV melanoma. J. Immunother. 32(6), 632–637 (2009).
    1. Dillman R, Selvan S, Schiltz P. et al. Phase I/II trial of melanoma patient-specific vaccine of proliferating autologous tumor cells, dendritic cells, and GM–CSF: planned interim analysis. Cancer Biother. Radiopharm. 19(5), 658–665 (2004).
    1. Dillman RO, Selvan SR, Schiltz PM. et al. Phase II trial of dendritic cells loaded with antigens from self-renewing, proliferating autologous tumor cells as patient-specific anti-tumor vaccines in patients with metastatic melanoma: final report. Cancer Biother. Radiopharm. 24(3), 311–319 (2009).

    2. • Results of single arm trial of dendritic cell vaccine in patients with metastatic melanoma, and doubling of median survival compared with historical control of similar patients treated with autologous irradiated tumor cell vaccine.

    1. Dillman RO, Cornforth AN, Depriest C. et al. Tumor stem cell antigens as consolidative active specific immunotherapy: a randomized Phase II trial of dendritic cells versus tumor cells in patients with metastatic melanoma. J. Immunother. 35(8), 641–649 (2012).
    1. Dillman RO, Cornforth AN, McClay EF. et al. Randomized Phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in patients with metastatic melanoma: 5-year follow up and additional analyses. J. Immunother. Cancer. 6(1), 19 (2018).

    2. • Results of randomized trial in patients with metastatic melanoma in which autologous dendritic cell vaccine was associated with doubling of median survival compared with patients treated with autologous irradiated tumor cell vaccine.

    1. Dillman RO, Depriest C. Dendritic cell vaccines presenting autologous tumor antigens from self-renewing cancer cells in metastatic renal cell cancer. J. Exploratory Res. Pharmacol. 3(4), 93–101 (2018).
    1. Wang X, Bayer ME, Chen X. et al. Phase I trial of active specific immunotherapy with autologous dendritic cells pulsed with autologous irradiated tumor stem cells in hepatitis B-positive patients with hepatocellular carcinoma. J. Surg. Oncol. 111(7), 862–867 (2015).
    1. Dillman RO, Nayak SK, Beutel L. Establishing in vitro cultures of autologous tumor cells for use in active specific immunotherapy. J. Immunother. Emphasis Tumor Immunol. 14(1), 65–69 (1993).
    1. Selvan SR, Carbonell DJ, Fowler AW. et al. Establishment of stable cell lines for personalized melanoma cell vaccine. Melanoma Res. 20(4), 280–292 (2010).
    1. Cornforth AN, Fowler AW, Carbonell DJ. et al. Characterization of interferon-γ-treated melanoma tumor cells for use in dendritic cell-based immunotherapy. Cancer Biother. Radiopharm. 26, 345–351 (2011).
    1. Cornforth AN, Lee G, Dillman RO. Autologous peripheral blood mononuclear cell recognition of autologous proliferating tumor cells in the context of a patient-specific vaccine trial. J. Biomed. Biotechnol. 2011, 635850 (2011).
    1. Balch CM, Gershenwald JE, Soong SJ. et al. Final version of 2009 AJCC melanoma staging and classification. J. Clin. Oncol. 27(36), 6199–6206 (2009).
    1. Tagawa ST, Cheung E, Banta W. et al. Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with stage IV melanoma. Cancer 106(6), 1353–1357 (2006).
    1. Schadendorf D, Hodi S, Robert C. et al. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33(17), 1889–1894 (2015).
    1. Topalian SL, Sznol M, McDermott DF. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32(10), 1020–1030 (2014).
    1. Schwartzentruber DJ, Lawson DH, Richards JM. et al. Gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 364(22), 2119–2127 (2011).
    1. Naidoo J, Page DB, Li BT. et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol. 26(12), 2375–2391 (2015).
    1. Wang PF, Chen Y, Song SY. et al. Immune-related adverse events associated with anti-PD1/PD-L1 treatment for malignancies: a meta-analysis. Front. Pharmacol. 18(8), 730 (2017).
    1. Baxi S, Yang A, Gennarelli RL. Immune-related adverse events for anti-PD-1 and anti-PD-L-1 drugs: systematic review and meta-analysis. BMJ 360, k793 (2018).
    1. Muranski P, Boni A, Antony PA. et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112(2), 362–373 (2008).
    1. Kryczek I, Banerjee M, Cheng P. et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114(6), 1141–1149 (2009).
    1. Dillman RO, DePriest C, DeLeon C. et al. Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory Phase I/II trials in patients with metastatic melanoma. Cancer Biother. Radiopharm. 22(3), 309–321 (2007).
    1. Robert C, Karaszewska B, Schachter J. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372(1), 30–39 (2015).
    1. Long GV, Weber JS, Infante JR. et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J. Clin. Oncol. 34(8), 871–878 (2016).
    1. Long GV, Flaherty KT, Stroyakovskiy D. et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a Phase III study. Ann. Oncol. 28(7), 1631–1639 (2017).
    1. Robert C, Long GV, Brady B. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372(4), 320–330 (2015).
    1. Robert C, Schachter J, Long GV. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372(26), 2532–2532 (2015).
    1. Weber JS, Hodi FS, Wolchok JD. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35(7), 7885–792 (2017).
    1. Ribas A, Puzanov I, Dummer R. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-0002): a randomised, controlled, Phase II trial. Lancet Oncol. 16(8), 908–918 (2015).
    1. Ribas A, Hamid O, Daud A. et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315(15), 1600–1609 (2016).
    1. Eggermont AM, Chiarion-Sileni V, Grob JJ. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375(19), 1845–1855 (2016).
    1. Long GV, Hauschild A, Santinami M. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377(19), 1813–1823 (2017).
    1. Weber J, Mandala M, Del Vecchio M. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377(19), 1824–1835 (2017).
    1. Eggermont AM, Blank CU, Mandala M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378(19), 1789–1801 (2018).
    1. Postow MA, Chesney J, Pavlick AC. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372(21), 2006–2017 (2015).
    1. Larkin J, Chiarion-Sileni V, Gonzalez R. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
    1. Wolchok JD, Chiarion-Sileni V, Gonzalez R. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377(14), 1345–1356 (2017).
    1. Zabierowski SE, Herlyn M. Melanoma stem cells: the dark seed of melanoma. J. Clin. Oncol. 26(17), 2890–2894 (2008).
    1. Schmidt P, Kopecky C, Hombach A. et al. Eradication of melanomas by targeted elimination of a minor subset of tumor cells. Proc. Natl Acad. Sci. USA 108(6), 2474–2479 (2011).
    1. Ning N, Pan Q, Zheng F. et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 72(7), 1853–1864 (2012).

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever