Immunotherapy of Myelodysplastic Syndrome: You Can Run, but You Can't Hide Ephraim Joseph Fuchs

Published OnlineFirst December 28, 2017; DOI: 10.1158/1078-0432.CCR-17-2960 CCR Translations Clinical Cancer Research Immunotherapy of Myelodysplastic Syndrome: You Can Run, but You Can't Hide Ephraim Joseph Fuchs The hypomethylating agent decitabine induces expression of the specific T-cell responses directed against their abnormal myeloid cancer/testis antigen NY-ESO-1 in the myeloid cells of patients cells, raising hopes for combinatorial immunotherapy of this with myelodysplastic syndrome (MDS). Patients with MDS treated disease. Clin Cancer Res; 24(5); 991–3. Ó2017 AACR. with decitabine and an NY-ESO-1 vaccine developed NY-ESO-1– See related article by Griffiths et al., p. 1019 In this issue of Clinical Cancer Research,Griffiths and collea- prostate, ovary, or pancreas, generally respond poorly to CIs. The gues conduct a phase I clinical trial in patients with myelo- major limitation to CAR T cells is that the target of the chimeric dysplastic syndrome (MDS) of a combinatorial immunother- receptor must be expressed on the cell surface, yet there are no apy (Fig. 1) comprising the hypomethylating agent decitabine cell surface molecules that distinguish a cancer cell from its plus a vaccine against the "cancer/testis" antigen NY-ESO-1 (1). normal tissue counterpart. Thus, CAR T cells are tissue specific This strategy addresses a critical, unmet need in cancer immu- rather than tumor specific and can only be used to treat cancers notherapy: the treatment of cancers with few available immu- deriving from tissues, such as B lymphocytes, that are not nologic targets. essential to the survival of the patient. The success of the immunologic checkpoint inhibitors (CI) So, what can be done to stimulate an effective antitumor and of chimeric antigen receptor–modified T cells, or CAR T immune response against cancers with no unique targets on the cells, has raised the level of enthusiasm for cancer immuno- cell surface and a low mutational burden? This is the challenge therapy to a fever pitch. Studies on the mechanism of the that Griffiths and colleagues confronted in developing an antitumor effect of the anti–CTLA-4 antibody ipilimumab or approach to the immunotherapy of MDS (1). MDS is a clonal the anti–PD-1 antibodies nivolumab or pembrolizumab have hematopoietic disorder characterized by ineffective hematopoi- shown that these CIs stimulate endogenous (i.e., patient- esis and an inexorable progression to acute myeloid leukemia derived) T cells specific for tumor "neoantigens" (2), tumor- (AML). Because the molecules on the surface of MDS cells are specific antigens that result from somatic mutation. The reac- all expected to be expressed on normal white blood cells, it tivity of CAR T cells against tumor cells is achieved by inserting would be difficult if not impossible to target MDS with CAR T into T cells a receptor whose extracellular domain consists of cells without unacceptable toxicities. Furthermore, MDS is char- the antigen-binding portion of an antibody reactive to a mol- acterized by a low mutational burden, and CIs have only modest ecule on the tumor cell surface while the intracellular portion activity against this disease (5). triggers the cytolytic machinery of the T cell. Thus, CAR T cells The only approved therapies for MDS are the hypomethylating combine the exquisite specificity of antibodies for protein agents azacitidine and decitabine. Although their mechanism of antigens with the lethality of cytotoxic T cells. action has not been fully defined, several lines of evidence suggest Still, there are major obstacles to the broad application of that demethylation of promoter regions enables the reexpression immunotherapy to the treatment of several common tumor of potentially immunogenic proteins, leading to a therapeutic types. For example, the efficacy of CIs is limited primarily to antitumor immune response. One such protein with inducible tumors with large numbers of clonal mutations (3). Even in expression on myeloid cells is the cancer/testis antigen NY-ESO-1. tumors with a high mutational burden, such as melanoma or Cancer/testis antigens are a heterogeneous group of proteins that lung cancer, response rates to CIs rarely exceed 50%, and clonal are normally expressed in germ cells and in diverse types of escape from immunosurveillance or active resistance mechan- cancers, but not in differentiated tissues of the adult. However, isms are common (4). Tumors with low numbers of somatic NY-ESO-1 is constitutively expressed in up to one third of patients mutations, such as pediatric cancers or cancers of the breast, with melanoma and lung, esophageal, liver, gastric, prostate, ovarian, or bladder cancers (6), and antibodies against NY- ESO-1 can be found in the serum of such patients. In patients Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, with MDS or AML, the promoter region of the NY-ESO-1 gene is Maryland. heavily methylated, and so the protein is not usually made in the Corresponding Author: Ephraim Joseph Fuchs, Division of Hematologic Malig- malignant cells. nancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 289 In a previous study, the authors showed that the expression Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21287. Phone: 410- ofcancer/testisantigensNY-ESO-1andMAGEA3/A6isinduced 955-8143; Fax: 410-614-3809; E-mail: [email protected] on AML blasts in patients treated with decitabine (7). This doi: 10.1158/1078-0432.CCR-17-2960 finding raised the possibility that decitabine could be used to Ó2017 American Association for Cancer Research. increase NY-ESO-1 expression in blasts while a vaccine against www.aacrjournals.org 991 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 28, 2017; DOI: 10.1158/1078-0432.CCR-17-2960 Fuchs CD141+ DC poly-ICLC NY-ESO-1– Figure 1. specific Combinatorial strategy to sensitize CDX-1401 CD8+ T cell neoplastic myeloid cells of MDS patients to killing by T cells specific DEC-205 for the cancer/testis antigen NY-ESO-1. Decitabine demethylates TLR3 NY-ESO-1 NY-ESO-1– the promoter region of the specific gene, leading to upregulation of transcription and translation of the CTL NY-ESO-1 protein in neoplastic myeloid cells (bottom). Meanwhile, the CDX-1401 vaccine, a fusion protein containing the full-length NY-ESO-1 protein, linked to an antibody against the dendritic cell (DC) surface molecule DEC-205, is taken into CD141HI DCs as the DCs are NY-ESO-1 being activated by the adjuvant, poly-ICLC, binding to the intracellular Toll-like receptor, TLR3. Gene expression Once taken into the cell, the fusion repressed Gene expression protein is processed by the CpG island NY-ESO-1 CpG island NY-ESO-1 proteasome and peptides of NY- ESO-1 are presented in the context of Myeloid cell major histocompatibility molecules Myeloid cell to NY-ESO-1–specific CD4þ (not shown) and CD8þ T cells. Activated CD8þ cytotoxic T lymphocytes (CTL) can then secrete IFNg and kill neoplastic myeloid cells presenting the cognate NY-ESO-1 peptide. Decitabine © 2017 American Association for Cancer Research NY-ESO-1 could be administered to generate a cytotoxic T-cell nation. First, there was not a consistent correlation between response from autologous T cells specific for this antigen. In the immunologic and clinical responses. The patient with the best current study, Griffiths and colleagues conducted a phase I trial immunologic response to treatment achieved a durable complete in which nine patients with MDS received an HLA-unrestricted remission, but the next best immunologic responder (patient 2) NY-ESO-1 vaccine (CDX-1401 þ poly-ICLC) every 4 weeks with only had stable disease following treatment. Second, one patient standard-dose decitabine. NY-ESO-1 expression was induced in (patient 6) expressed NY-ESO-1 in myeloid cells prior to decita- all seven patients who reached the end of the study, and NY- bine treatment, but this was not associated with an endogenous þ þ ESO-1–specificCD4 and CD8 T-cell responses were seen in immune response. Finally, another patient (patient 7) experienced six of seven and four of seven vaccinated patients, respectively a durable complete remission despite a relatively weak induction þ þ (1). Myeloid cells, isolated from a patient at different time of CD4 T cells and no induction of CD8 T cells. One explana- points during decitabine therapy, expressed NY-ESO-1 and tion for dissociation between NY-ESO-1 expression and response activated cytotoxicity from autologous, NY-ESO-1–specificT to vaccination is that some patients may be immunologically cells. The intensity of the T- and B-cell response to NY-ESO-1 tolerant of NY-ESO-1. Although NY-ESO-1 is generally not vaccination was somewhat heterogeneous but appeared to expressed in adult tissues, it has been found to be expressed in correlate with the prevaccination frequency of dendritic cells the medullary thymic epithelium (8), where it can induce toler- (DC) that express the cell-surface marker CD141. Perhaps this ance in developing T cells. Indeed, cancer/testis antigen–specific correlation is not surprising, as these DCs express high levels of T cells isolated from cancer patients often have suboptimal affinity DEC-205, which is targeted by the vaccine, and TLR3, which is and do not mediate significant killing (9), suggesting that high- targeted by the vaccine adjuvant. Finally, a clinical response to affinity clones have been physically or functionally deleted from decitabine plus NY-ESO-1 vaccination was associated with an the repertoire. Although this finding may bode poorly for strategies increase in the frequency of CD141HI DCs in the bone marrow. of cancer vaccination, decitabine-induced expression of cancer/ Although the results of this combinatorial strategy are encour- testis antigens could be combined effectively with adoptive immu- aging, some observations need further characterization and expla- notherapy with high-affinity T cells specific for these antigens.

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