Abstract
Although significant therapeutic improvement has been achieved in the last 10 years, the survival of metastatic colorectal cancer patients remains in a range of 28 to 30 months. Presently, systemic treatment includes combination chemotherapy with oxaliplatin and/or irinotecan together with a backbone of 5-fluorouracil/levofolinate, alone or in combination with monoclonal antibodies to VEGFA (bevacizumab) or EGF receptor (cetuximab and panitumumab). The recent rise of immune checkpoint inhibitors in the therapeutic scenario has renewed scientific interest in the investigation of immunotherapy in metastatic colorectal cancer patients. According to our experience and view, here, we review the immunological strategies investigated for the treatment of this disease, including the use of tumor target-specific cancer vaccines, chemo-immunotherapy and immune checkpoint inhibitors.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 GLOBOCAN 2000. Cancer incidence mortality and prevalence worldwide, IARC, cancer base No 5, version 1.0. IARC Press, Lyon, France (2001).
- 2 . Systemic therapy for colorectal cancer. N. Engl. J. Med. 352(5), 476–487 (2005).
- 3 . The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development. Oncologist 15(1), 73–84 (2010).
- 4 . Immune checkpoint inhibitors in lung cancer: past, present and future. Future Oncol. 12(9), 1151–1163 (2016).
- 5 . The present status and future prospects of peptide-based cancer vaccines. Int. Immunol. 28(7), 319–328 (2016). • An overview defining the role of peptide-based active immunotherapy.
- 6 . Regulatory T cells and immune tolerance. Cell 133(5), 775–787 (2008).
- 7 . CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity. Immunol. Rev. 272(1), 52–64 (2016).
- 8 . T cell recognition of transforming proteins encoded by mutated ras protooncogenes. J. Immunol. 146, 2059–2065 (1991).
- 9 . Scheme for ranking potential HLAA2 binding peptides based on independent binding of individual peptide side-chains. J. Immunol. 152, 163–175 (1994).
- 10 . Costimulation of T cells for tumor immunity. Immunol. Today 14(10), 483–486 (1993).
- 11 CD28 costimulation: from mechanism to therapy. Immunity 44(5), 973–988 (2016).
- 12 Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J. Clin. Oncol. 18(1), 148–157 (2000).
- 13 Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized Phase III trials show promise. Vaccine 19(17–19), 2576–2582 (2001).
- 14 Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review. J. Transl. Med. 9, 17 (2011). • A meta-analysis defining the role of active immunotherapy in colorectal cancer (CRC) patients with minimal disease.
- 15 Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. Int. J. Cancer. 136(1), 127–137 (2015).
- 16 . Heat shock protein-peptide and HSP-based immunotherapies for treatment of cancer. Front. Immunol. 7, 171 (2016).
- 17 Vaccination with autologous tumor derived heat shock proten gs96 after liver resection for metastatic colorectal cancer. Clin. Cancer. Res. 9, 3235–3245 (2003).
- 18 . First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology 5(1), e1115641 (2015).
- 19 Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin. Cancer Res. 2(1), 21–28 (1996).
- 20 . Recombinant cancer vaccines based on viral vectors. Dev. Biol. (Basel). 116, 117–122; discussion 133–143 (2004).
- 21 . Carcinoembryonic antigen-based vaccines. Semin. Oncol. 30(3 Suppl. 8), 30–36 (2003).
- 22 . Colorectal cancer immunotherapy. Disc. Med. 15(84), 301–308 (2013). • An overview defining the role of active immunotherapy in metastatic (m)CRC patients.
- 23 Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin. Cancer Res. 14(15), 4843–4849 (2008).
- 24 Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J. Clin. Oncol. 23(4), 720–731 (2005).
- 25 . Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5-fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer. Cancer Res. 11(16), 5993–6001 (2005).
- 26 Recognition of carcinoembryonic antigen peptide and heteroclitic peptide by peripheral blood T lymphocytes. J. Immunother. 30(3), 350–358 (2007).
- 27 A randomized Phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. Ann. Surg. 258(6), 879–886 (2013).
- 28 A Phase I study of AD5-GUY2C-PADRE in stage I and II colon cancer patients. J. Immunother. Cancer 3(Suppl. 2), P450 (2015).
- 29 In vitro generation of cytotoxic T lymphocytes against HLA-A2.1-restricted peptides derived from human thymidylate synthase. J. Chemother. 13(5), 519–526 (2001).
- 30 5-Fluorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine. J. Natl Cancer Inst. 97(19), 1437–1445 (2005). •• A study defining the preclinical rationale for thymidylate synthase poly-epitope peptide (TSPP) vaccination alone or in combination with chemotherapy in cancer patients.
- 31 Chemotherapeutic drugs may be used to enhance the killing efficacy of human tumor antigen peptide specific CTLs. J. Immunother. 31, 132–147 (2008). • A study defining the preclinical rationale for TSPP vaccination in combination with chemoimmunotherapy in mCRC patients.
- 32 Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients. Cancer Immunol. Immunother. 64(9), 1159–1173 (2015). • A study defining the safety and immune-biological activity of TSPP peptide vaccination in advanced cancer patients.
- 33 Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients. Oncoimmunology 5(4), e1101205 (2015). •• A study defining the safety and immune-biological activity of TSPP peptide in combination with chemoimmunotherapy in mCRC patients.
- 34 Pseudomonas aeruginosa injection enhanced antitumor cytotoxicity of cytokine-induced killer cells derived from cord blood. Biomed. Pharmacother. 68(8), 1057–1063 (2014).
- 35 HIV vaccine development by computer assisted design: the GAIA vaccine. Vaccine. 23(17–18), 2379–2387 (2005).
- 36 Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol. Immunother. 58(1), 61–69 (2009).
- 37 A Phase I trial of cytotoxic T-lymphocyte precursor-oriented peptide vaccines for colorectal carcinoma patients. Br. J. Cancer 90(7), 1334–1342 (2004).
- 38 The immunological and clinical effects of mutated raspeptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J. Transl. Med. 12, 55 (2014).
- 39 A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine incolorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin. Cancer Res. 16(22), 5548–5556 (2010).
- 40 Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEAmRNA for vaccination of colorectal cancer patients. Anticancer Res. 30(12), 5091–5097 (2010).
- 41 Immune response, safety, and survival and qualityof life outcomes for advanced colorectal cancer patients treated with dendriticcell vaccine and cytokine-induced killer cell therapy. BioMedRes. Intl 2014, 603871 (2014).
- 42 Autologous tumor lysate-pulsed dendritic cell immunotherapy withcytokine-induced killer cells improves survival in gastric and colorectal cancer patients. PloS ONE 9(4), e93886 (2014).
- 43 Vaccination of colorectal cancerpatients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a Phase I/II trial. Clin. Cancer Res. 12(11 Pt 1), 3416–3424 (2006).
- 44 An MVA-based vaccinetargeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases. J. Immunother. 31(9), 820–829 (2008).
- 45 Novel adenoviral vector induces T-cell responses despiteanti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol. Immunother. 62(8), 1293–1301 (2013).
- 46 Phase I study of single-agentanti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28(19), 3167–3175 (2010).
- 47 Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–2465 (2012).
- 48 PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015). •• A study defining the role of immune checkpoint inhibitors in mCRC patients.
- 49 Immune-modulating effects of the newest cetuximab-based chemoimmunotherapy regimen in advanced colorectal cancer patients. J. Immunother. 35(5), 440–447 (2012).
- 50 Immune-boost with gemcitabine, oxaliplatin, levofolinate, 5-flurouracil, granulocyte/macrophage colony-stimulating-factor (GM-CSF) and aldesleukine (GOLFIG) enhances progression-free and overall-survival over FOLFOX chemotherapy in metastatic colorectal cancer patients: GOLFIG-2 multi-centric open label randomized Phase III trial. J. Immunotherapy. 37(1), 26–35 (2014). •• A study defining the antitumor efficacy of frontline GOLFIG chemoimmunotherapy over standard treatments in mCRC patients.
- 51 The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 22(6), 624–631 (2016). • A preclinical study defining the immune-biological effects of cetuximab with potential antitumor activity in mCRC patients.
- 52 Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J. Immunol. 175(2), 820–828 (2005). •• A study defining the preclinical rationale for gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, GM-CFS, IL-2 (GOLFIG) chemoimmunotherapy in mCRC patients.
- 53 Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J. Clin. Oncol. 23(35), 8950–8958 (2005). • A study defining the antitumor activity of GOLFIG chemoimmunotherapy in mCRC patients.
- 54 Immunity feedback and clinical outcome in colon cancer patients undergoing chemo-immunotherapy with gemcitabine + FOLFOX followed by subcutaneous granulocyte macrophage-colony stimulating factor and aldesleukine (GOLFIG-1 trial). Clin. Cancer Res. 14(13), 4192–4199 (2008). • A study defining the role of autoimmunity in predicting the outcome of GOLFIG chemoimmunotherapy in mCRC patients.
- 55 . Immunomodulatory properties of anticancer monoclonal antibodies: is the magic bullet’ still a reliable paradigm? Immunother. 3, 1–4 (2011). • An overview defining the immune-biological effects of monoclonal antibodies with potential antitumor activity in cancer patients.
- 56 Cetuximab+/−chemotherapy enhances dendritic cell-mediated phagocytosis of colon cancer cells and ignites a highly efficient colon cancer antigen-specific cytotoxic T-cell response in vitro. Int. J. Cancer. 130, 1577–1589 (2011). • A preclinical study defining the immune-biological effects of cetuximab with potential antitumor activity in mCRC patients.
- 57 . Advances in cancer immunology and cancer immunotherapy. Discov. Med. 21(114), 125–133 (2016). •• A critical overview defining the recent advances in cancer immunotherapy.
- 58 . Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. J. Clin. Invest. 125(9), 3377–3383 (2015).
- 59 . The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation. Curr. Opin. Oncol. 26(2), 204–214 (2014).
- 60 Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 4(13), 211 (2015).
- 61 Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 28(21), 3485–3490 (2010).
- 62 Programmed death-1 & its ligands: promising targets for cancer immunotherapy. Immunother. 7(7), 777–792 (2015).
- 63 ESMO/ECCO 2015: the highlights of immunotherapy and targeted therapies. Bull. Cancer 103(6), 594–603 (2016). •• A critical overview defining the recent advances in cancer immunotherapy and immune checkpoint inhibitors.
- 64 . The potential role of immunotherapy to treat colorectal cancer. Expert. Opin. Investig. Drugs 24(3), 329–344 (2015).
- 65 . Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges. Immunother. 8(7), 821–837 (2016). •• A critical overview defining the recent advances in cancer immunotherapy with immune checkpoint inhibitors.
- 66 The impact of mismatch repair status in colorectal cancer on the decision to treat with adjuvant chemotherapy: an Australian population-based multicenter study. Oncologist 21(5), 618–625 (2016).
- 67 Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity. 44(3), 698–711 (2016). •• A critical study defining the role in immunoscore in predicting the outcome of mCRC patients.
- 68 . Platinum-based chemotherapy: gastrointestinal immunomodulation and enteric nervous system toxicity. Am. J. Physiol. Gastrointest. Liver Physiol. 308(4), G223–G232 (2015).
- 69 Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75(13), 2629–2640 (2015).
- 70 Myeloid-derived suppressor cells reveal radioprotective properties through arginase-induced l-arginine depletion. Radiother. Oncol. 119(2), 291–299 (2016).
- 71 The clinical and prognostic significance of CD14(+)HLA-DR (−/low) myeloid-derived suppressor cells in hepatocellular carcinoma patients receiving radiotherapy. Tumour Biol. 37(8), 10427–10433 (2016).
- 72 . Myeloid-derived cells in tumors: effects of radiation. Semin. Radiat. Oncol. 25(1), 18–27 (2015).
- 73 Colorectal cancer and immunity: what we know and perspectives. World J. Gastroenterol. 20(14), 3738–3750 (2014).
- 74 Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 28(6), 690–714 (2015). •• A critical study defining the immunological effects of immunological effects of chemotherapy and targeted anticancer agents.
- 75 Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology 3(1), e27878 (2014). • A study defining the immunological effects of immunological effects of chemotherapy.
- 76 Control of the immune response by pro-angiogenic factors. Front. Oncol. 4, 70 (2014). • A study defining the immune-adjuvant effects of VEGF depletion.
- 77 The route to solve the interplay between inflammation, angiogenesis and anti-cancer immune response. Cell Death Dis. 7, e2299 (2016). • A study defining the immune-adjuvant effects of bevacizumab and its effect of tumor-associated inflammation.
- 78 Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology 3(12), e968434 (2015). •• A critical study defining the immunological effects of radiotherapy.
- 79 Radiotherapy combined with immune checkpoint blockade immunotherapy: achievements and challenges. Cancer Lett. 365(1), 23–29 (2015). • An overview defining the immunological effects of radiotherapy and future perspective.
- 80 External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 64, 4328–4337 (2004).