Cancer immunotherapy: Targeting the difference
Authors: Sarene Koh, Antonio Bertoletti
Journal: Journal of Hepatology (2014)

COMMENTARY ON: Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Science. 2014 May 9;344(6184):641–645. © (2014) Reprinted with permission from AAAS. http://www.ncbi.nlm.nih.gov/pubmed/24812403 Abstract: Limited evidence exists that humans mount a mutation-specific T cell response to epithelial cancers. We used a whole-exomic-sequencing-based approach to demonstrate that tumour-infiltrating lymphocytes (TILs) from a patient with metastatic cholangiocarcinoma contained CD4+ T helper 1 (TH1) cells, recognizing a mutation in the erbb2 interacting protein (ERBB2IP) expressed by the cancer. After adoptive transfer of TILs, containing about 25% mutation-specific polyfunctional TH1 cells, the patient achieved a decrease in target lesions with prolonged stabilization of the disease. Upon disease progression, the patient was retreated with a >95% pure population of mutation-reactive TH1 cells and again experienced tumour regression. These results provide evidence that a CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer. T cell based cancer immunotherapy, the concept of utilizing T cells to cure cancer patients, was until recently regarded with scepticism. One of the main conceptual problems is that, physiologically, T cells recognize and eliminate cells that express non-self proteins. These are not usually present in cancer cells that instead express so called "tumour-associated antigens", which are self-antigens expressed at different levels in cancer vs. normal cells [1Finn O.J. Cancer immunology.N Engl J Med. 2008; 358: 2704-2715Crossref PubMed Scopus (733) Google Scholar, 2Coulie P.G. Van den Eynde B.J. Van der Bruggen P. Boon T. Tumor antigens recognized by T lymphocytes: at the core of cancer immunotherapy.Nat Rev Cancer. 2014; 14: 135-146Crossref PubMed Scopus (781) Google Scholar]. There are immunological consequences of this feature: tumour-associated antigens are poor inducers of tumour-specific T cells that do not expand in patients or poorly recognize the tumour cells. A second consequence is that if and when tumour-associated antigen-specific T cells are efficiently produced (for example by engineering T cells with a chimeric T cell receptor (TCR) specific for tumour-associated antigens), the T cells will not only target the tumour but also normal cells with a clinical outcome that might be extremely severe [[3]Morgan R.A. Yang J.C. Kitano M. Dudley M.E. Laurencot C.M. Rosenberg S.A. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol Ther. 2010; 18: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1802) Google Scholar]. However, the concept that cancerous cells do not express immunogenic non-self antigens changed after the demonstration that the genetic alterations present in cancers can lead to the production of new immunogenic "non-self" antigens that can be exploited to induce effective tumour-specific T cell responses. T cell specific tumour-associated neo-antigens were detected in melanoma and were suggested to be the cause of the high immunogenicity of this cancer. In this new paper, Tran et al., make the very important demonstration that such "neo antigens" are present and immunogenic not only in melanoma but also in a cancer of epithelial origin, which account for 80% of all human cancers. Furthermore, they not only demonstrated that T cells recognizing a mutated version of a tumour-associated antigen can be detected in a patient with metastatic cholangiocarcinoma but also that these mutation-specific T cells unique to the patient's cancer can be harnessed to mediate regression of a metastatic epithelial cancer (Fig. 1). To demonstrate the presence of mutation-specific T cells, the authors first used a leading edge whole-exome sequencing based approach to identify mutated candidate epitopes expressed in lung metastases of a patient with bile duct cancer not responsive to standard chemotherapy. The 26 detected mutated sequences were expressed on autologous antigen presenting cells using constructed libraries of minigenes encoding the mutated sequences. They then tested whether the patient's tumour-infiltrating lymphocytes (TILs) recognized any of these mutations and demonstrated that T cells infiltrating the patient's tumour comprised of T cells that recognized only a mutated version of the ERBB2-interacting protein (ERBB2IP) but were unresponsive to the wild type non-mutated ERBB2IP. These mutation-specific T cells were CD4 cells, HLA-DQB1∗0601 restricted, recognized a minimal epitope composed of 13 amino acids and seemed to be of mono-oligoclonal origin since they were characterized for a very restricted TCR usage. Direct evidences that these mutation-specific T cells can be exploited for therapeutic purpose were obtained by showing that adoptive cell transfer of a large quantity (42.4 billion) of the expanded TILs, of which about 25% were CD4+ ERBB2IP mutation-reactive T lymphocytes caused tumour regression and disease stabilization for approximately one year. This clinical efficacy was confirmed after a second round of adoptive T cell therapy in which 95% of the transferred cells were Vβ22+ ERBB2IP mutation-reactive TH1 cells that caused an accelerated tumour regression. Therefore, by demonstrating that mutations present in epithelial tumours produced new antigens able to induce T cells that recognize the patient-specific mutated protein, Tran et al. bring to the forefront an alternative strategy to generate T cells for adoptive cell therapy and treat patients with common epithelial cancers, where there is a low frequency of tumour-reactive T cells. The results presented in this study are also encouraging as CD4+ TH1 cells, other than CD8 CTL, can confer clinical benefit in targeting cancer. Targeting sporadic or driver mutations unique to a patient's individual cancer with mutation-reactive T cells has also the advantage to cause minimal "off-target" reactivity (cross-reactivity) and thus avoiding the severe side effects that have been described in some recent cancer immunotherapy trials [4Morgan R.A. Chinnasamy N. Abate-daga D. Gros A. Robbins P.F. Zheng Z. et al.Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.J Immunother. 2013; 36: 133-151Crossref PubMed Scopus (830) Google Scholar, 5Linette G.P. Stadtmauer E.A. Maus M.V. Rapoport A.P. Levine B.L. Emery L. et al.Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.Blood. 2013; 122: 863-871Crossref PubMed Scopus (797) Google Scholar]. Despite the remarkable results, the data have been obtained from a single patient and the feasibility of such a method has to be evaluated in more patients with different epithelial cancers to analyze the extent to which tumour mutations can be targeted by adoptive T cell therapy. Furthermore, the approach described in this report is perhaps limited to cancers where there are few mutations, as screening hundreds of mutations for immunogenicity is technically challenging with the current technology and there is also the risk that an already genetically unstable tumour might simply escape the immune attack via downregulation of the target protein. There has been evidence in human studies suggesting that effective immunotherapy might lead to cancer immunoediting [6Rosenberg S.A. Yang J.C. Robbins P.F. Wunderlich J.R. Sherry R.M. Schwartzentruber D.J. et al.Cell transfer therapy for cancer: lessons from sequential treatments of a patient with metastatic melanoma.J Immunother. 2003; 26: 385-393Crossref PubMed Scopus (58) Google Scholar, 7Khong H.T. Wang Q.J. Rosenberg S.A. Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression.J Immunol. 2004; 27: 184-190Google Scholar]. Given the heterogeneity of the majority of cancers, it is difficult to predict if targeting a single mutation epitope might result in durable tumour control or selection of immunoresistant tumour variants that might accelerate tumour progression [[8]Kessler J.H. Melief C.J.M. Identification of T-cell epitopes for cancer immunotherapy.Leukemia. 2007; 21: 1859-1874Crossref PubMed Scopus (107) Google Scholar]. Nevertheless, the authors commented that "mapping of the mutational landscape of human cancer is occurring at rapid pace but clinical strategies to exploit such knowledge for clinical benefit remain to be realized"; perhaps in the near future it might be possible to apply multi-epitope-based cancer immunotherapies in the clinic. This pioneering work opens the new exciting possibility to develop real personalized immune based targeted therapy for many different cancers. Sequences of proteins expressed by tumours could be used to detect mutations or the presence of other "non-self proteins" like for example viral antigens, that should be highly represented in hepatitis B virus (HBV)-related HCC (where a high frequency of HBV-DNA integration is known to occur) [[9]Sung W.-K. Zheng H. Li S. Chen R. Liu X. Li Y. et al.Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.Nat Genet. 2012; 44: 765-769Crossref PubMed Scopus (662) Google Scholar], and target them with T cells expanded from the tumours or T cells engineered to express specific T cell receptors [[10]Koh S. Shimasaki N. Suwanarusk R. Ho Z.Z. Chia A. Banu N. et al.A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus.Mol Ther Nucleic Acids. 2013; 2: e114Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. The experimental framework to translate such knowledge into new therapies has been provided. The realization of clinical benefits for cancer patients might not be such a distant reality. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.