Mol. Cells

Clinical Perspectives to Overcome Acquired Resistance to Anti–Programmed Death-1 and Anti–Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer

Yong Jun Lee, Jii Bum Lee, Sang-Jun Ha, and Hye Ryun Kim

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Abstract

Immune checkpoint inhibitors have changed the paradigm of treatment options for non-small cell lung cancer (NSCLC). Monoclonal antibodies targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have gained wide attention for their application, which has been shown to result in prolonged survival. Nevertheless, only a limited subset of patients show partial or complete response to PD-1 therapy, and patients who show a response eventually develop resistance to immunotherapy. This article aims to provide an overview of the mechanisms of acquired resistance to anti–PD-1/PD-L1 therapy from the perspective of tumor cells and the surrounding microenvironment. In addition, we address the potential therapeutic targets and ongoing clinical trials, focusing mainly on NSCLC.

Keywords: acquired resistance, immune checkpoint inhibitors, non-small cell lung cancer, programmed death-1, programmed death ligand-1

INTRODUCTION

Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte associated antigen-4 (CTLA-4), PD-1, and PD-L1 receptors have been shown to have beneficial therapeutic effects in lung cancer (Steven et al., 2016). ICIs are the first-line treatment for non-small cell lung cancer (NSCLC) with positive PD-L1 expression (Ettinger et al., 2019). However, only 20% to 30% of NSCLC patients are sensitive to anti–PD-1/PD-L1 therapy, and most patients experience resistance to immunotherapy (Pourmir et al., 2020). Acquired resistance is defined as disease progression within 6 months after a period of clinical benefit (Remon et al., 2020; Sharma et al., 2017). The mechanisms of acquired resistance remain to be fully elucidated, as research on treatment strategies to overcome resistance to approved immunotherapies is ongoing (Bagchi et al., 2021). Here, we discuss the mechanisms of acquired resistance to anti–PD-1/PD-L1 therapy in NSCLC, including loss of immunogenic neoantigens, upregulation of alternate immune checkpoint receptors, increase in immunosuppressive cells, cytokines, and immunoregulatory molecules in the tumor microenvironment, and epigenetic modifications. In addition, we have summarized the potential therapeutic targets and ongoing clinical trials.

MECHANISMS OF ACQUIRED RESISTANCE TO ANTI–PD-1/PD-L1

Loss of immunogenic neoantigen

B2M and MHC defects

Defects in beta-2-microglobulin (B2M) or major histocompatibility complex (MHC) molecules can cause decreased neoantigen presentation (Mariathasan et al., 2018; Sucker et al., 2014). B2M stabilizes the alpha subunits of the MHC-I protein, and a mutation in the B2M gene results in loss of neoantigen surface expression (Gettinger et al., 2017; Zaretsky et al., 2016). In NSCLC, acquired homozygous loss of B2M results in a lack of MHC-I expression on the cell surface, which results in acquired resistance to PD-1 therapy (Gettinger et al., 2017). In addition to loss of heterozygosity, deletions or point mutations in the B2M gene have been found to be important pathways for both primary and acquired resistance to ICIs (Gettinger et al., 2017; Pereira et al., 2017).

Defects in the IFN-γpathway

Targeting downstream factors, such as JAK1/2 and STAT, is a possible treatment option to overcome acquired resistance to anti–PD-1 therapy in lung cancer (Table 1). A combination of JAK-STAT or vascular endothelial growth factor (VEGF) inhibitors and immune checkpoint therapy can help control tumor growth in phosphatase and tensin homolog (PTEN)-mediated acquired resistance to immune checkpoint monotherapy (Peng et al., 2016; Toso et al., 2014). Dual inhibition of the JAK1,2/PD-L1 and STAT3/PD-L1 signaling pathways led to better immune cytolytic activity of NK cells toward hypoxia-induced castrate-resistant prostate cancer (CRPC) cells (Xu et al., 2018). However, the combination of anti–PD-1 therapy with JAK/STAT inhibitors has also been shown to reduce anti-tumor effects and tumor infiltrating lymphocyte (TIL) numbers (Ashizawa et al., 2019).

Table 1
Mechanisms of acquired resistance and potential therapeutic approaches

Upregulation of other immune checkpoint receptors

Immune checkpoint receptors are upregulated as a compensatory mechanism after immunotherapy. These mechanisms include T cell exhaustion, proliferation, migration, and cytokine secretion by CD8+ T cells (Thommen et al., 2015; Topalian et al., 2015). Immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), and T cell immunoreceptors with Ig and ITIM domains (TIGIT) create an immunosuppressive environment (Fig. 1, Table 1) (Toor et al., 2020). LAG-3 is expressed on TILs, and dual blockade of LAG-3 and PD-1 resulted in synergistic anti-tumor effects in preliminary models (Hellmann et al., 2016). TIM-3 was upregulated in both CD4+ and CD8+ T cells in patients with lung cancer refractory to anti–PD-1 therapy (Koyama et al., 2016). Similarly, TIGIT expression on tumor antigen-specific CD8+ T cells was observed in patients with melanoma after anti–PD-1 treatment (Chauvin et al., 2015).

Figure F1
Immune suppressive and immune stimulatory cell-favored niche.The immune suppressive environment (left) shows the 1) immune suppressive cells including Tregs and MDSCs, 2) the expression of immune suppressive cytokines, and 3) ...

Other immune checkpoint receptors such as B and T lymphocyte attenuator (BTLA), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and sialic acid-binding Ig-like lectin 9 (SIGLEC9) are also potential treatment targets (Galon and Bruni, 2019). Similarly, immune stimulatory agents such as OX40 and inducible T cell costimulatory (ICOS) agonists enhance T cell expansion and effector functions by controlling the tumor suppressive function of regulatory T cells (Tregs) (Hu-Lieskovan and Ribas, 2017; Mahoney et al., 2015).

Suppressive tumor microenvironment

Immunosuppressive cells

In patients refractory to anti–PD-1 therapy, decreased T cell effector function is associated with an increase in immunosuppressive cells such as Tregs, myeloid-derived suppressor cells (MDSCs), and tumor associated macrophages (TAM) (Fig. 1, Table 1) (Arlauckas et al., 2017). Tregs directly inhibit effector T cells (Teff) or produce inhibitory cytokines, such as interleukin (IL)-10, IL-35, and transforming growth factor-β (TGF-β), which suppress CD8+ T cells, resulting in acquired resistance to ICIs (Sakaguchi et al., 2008; Saleh and Elkord, 2019). MDSCs induce acquired resistance to ICIs via direct action on T cells, promotion of tumor angiogenesis, and recruitment of immune suppressive cells to the tumor microenvironment (Hou et al., 2020). MDSCs in the tumor microenvironment are related to a lack of response to immunotherapy (Meyer et al., 2014). M2 macrophages reshape the tumor microenvironment into a pro-tumorigenic environment (Chanmee et al., 2014). The colony-stimulating growth factor 1 receptor (CSF1R) plays a critical role in differentiation, proliferation, and survival of the mononuclear phagocyte system and macrophages (Stanley and Chitu, 2014). Blocking CSF1R results in a decrease in tumor-associated microphages, and addition of CSF1R inhibitor with PD1 and CTLA4 antagonists improves the response to ICIs in pancreatic cancer mouse models (Zhu et al., 2014), suggesting CSF1R inhibitor as a therapeutic approach for immunotherapy resistance.

Immunosuppressive cytokines

IL-6 and IL-8 are proinflammatory cytokines that are found in the tumor microenvironment. IL-6 decreases PD-L1 and MHC class 1 expression, leading to tumor evasion and ICI therapy resistance (Garcia-Diaz et al., 2017). IL-8 modulates chemotaxis of neutrophils, resulting in pro-tumorigenic effects (Alfaro et al., 2016). High concentrations of IL-8 inhibit T cell function and antigen presentation, thereby promoting resistance to ICI therapy (Yuen et al., 2020).

Immunoregulative molecules

Immunoregulatory molecules such as adenosine, indoleamine 2,3-dioxygenase 1 (IDO1), and B7-H4 contribute to immunosuppression, which is associated with ICI resistance (Table 1) (Platten et al., 2015; Zang et al., 2003; Zhang et al., 2004). Adenosine inhibits effector T cells and increases Tregs via adenosine A2A receptor (A2AR) binding, leading to a decrease in NK cell maturation and its action (Young et al., 2018). Blocking CD73 or A2AR prevents adenosine signaling and improves the response of tumor cells to anti–PD-1 therapy (Vijayan et al., 2017). IDO1 is an enzyme that converts tryptophan to kynurenine. Consumption of tryptophan and accumulation of kynurenine activates Teff and Tregs, and promotes Treg cell formation (Ricciuti et al., 2019). Combination of IDO inhibitors with ICI therapy enhances the TIL function and number in the tumor microenvironment (Spranger et al., 2014). B7-H4 binds to T cells and inhibits their proliferation, cytotoxic action, and interleukin secretion by T cells (Zang et al., 2003). In patients with advanced NSCLC, high expression of B7-H4 is associated with tumor progression and tumor-related death risks (Genova et al., 2019). The effect of B7-H4 on immunotherapy resistance remains to be fully elucidated.

Epigenetic modification

Epigenetic modifications are associated with anticancer immunity, including T cell function, migration, exhaustion, and neoantigen expression (Wang et al., 2020). Epigenetic modifications silence tumor suppressor and apoptosis genes, thereby activating tumor proliferation (Table 1) (Baxter et al., 2014). For instance, the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex decreases the sensitivity of tumor cells to CTLs, leading to a lack of response to immunotherapy (Miao et al., 2018; Pan et al., 2018). Several studies have demonstrated that re-invigoration of exhausted CD8+ T cells and memory T cells is feasible via chromatin remodeling and epigenetic modification (Fig. 1) (Jenkins et al., 2018; Pauken et al., 2016; Ribas et al., 2016).

POTENTIAL THERAPEUTIC STRATEGIES FOR OVERCOMING ACQUIRED RESISTANCE

Clinical trials on the IFN-γ pathway

Several clinical trials targeting JAK1/2 and STAT are ongoing. In a phase 1/2 study, AZD4205, a JAK1-selective inhibitor, was administered as both monotherapy and combination therapy with osimertinib in advanced NSCLC patients (NCT03450330). A phase 1/2 clinical trial of SC-43, an SHP-1 agonist that inhibits STAT3, in combination with cisplatin therapy for NSCLC is ongoing (NCT04733521).

Activation of stimulator of IFN genes (STING) showed an increase in anti-tumor immunity via the upregulation of proinflammatory chemokines and cytokines, including type I IFNs (Su et al., 2019). STING agonists are a promising option for patients with resistance to immunotherapy. Clinical trials of STING agonists for solid tumors, such as E7766, GSK3745417, and MIW815, are ongoing (NCT04144140, NCT03843359, and NCT03172936, respectively).

Clinical trials targeting other immune checkpoints

Randomized, double-blind, and phase 2 clinical trial of anti-TIGIT antibody tiragolumab in combination with atezolizumab (PD-L1 inhibitor) compared with placebo plus atezolizumab in patients with PD-L1-selected NSCLC (CITYSCAPE) revealed improvement in overall response rates (ORR; 31.3% for tiragolumab group and 16.2% for placebo group) and mean progression free survival (mPFS; 5.4 months for tiragolumab group and 3.6 months for placebo group) (Rodriguez-Abreu et al., 2020). Other agents targeting immune checkpoint receptors are currently under investigation (Table 2).

Table 2
Clinical trials of investigational agents on acquired resistance

Clinical trials targeting tumor microenvironment

The A2AR antagonist CPI-444 showed anti-tumor effects as both monotherapy and combination therapy with atezolizumab in patients with anti–PD-1/PD-L1 treatment-refractory renal cell carcinoma (RCC) and NSCLC, with a disease control rate of 36% for monotherapy in NSCLC and 71% for combination therapy in NSCLC (Fong et al., 2017). Other agents targeting the tumor microenvironment, such as CSF1R, TGF-β, VEGF, IL-1/6, A2AR, CD73, IDO1, and B7-H4 inhibitors, are listed in Table 2.

Clinical trials on epigenetic modification

Epigenetic modifications include DNA methylation and histone (Kim et al., 2020). DNA methylation is mediated by DNA methyltransferase (DNMT), which regulates silencing of genes and non-coding genomic regions. Histone modification enzymes such as histone methyltransferase (HMT) and histone deacetylase (HDAC) change the structure of chromatin, leading to gene regulation and carcinogenesis (Kanwal and Gupta, 2012). Epigenetic modification enzyme inhibitors such as DNA methyltransferase inhibitors (DNMTis), histone methyltransferase inhibitors (HMTis), and histone deacetylase inhibitors (HDACis) are potential therapeutic targets for immunotherapy resistance (Arenas-Ramirez et al., 2018). Preclinical studies have shown that both DNMTi and HDACi increase the response to anti–PD-1 therapy in various tumors (Mazzone et al., 2017). One of the histone methyltransferase enzymes, enhancer of zeste homolog 2 (EZH2), is involved in the proliferation, migration, and invasion of various cancer cells such as glioblastoma, ovarian cancer, and prostate cancer (Yamaguchi and Hung, 2014). EZH2 exhibited a silencing effect on antigen presentation and immune reaction, and blocking of EZH2 resulted in synergistic effects with anti–CTLA-4 and IL-2 immunotherapy (Zingg et al., 2017).

For patients with relapsed or refractory malignant mesothelioma, the EZH2 inhibitor tazemetostat was well tolerated and showed a 47% disease control rate in 12 patients (Zauderer et al., 2020). A phase 1/2 clinical trial of tazemetostat monotherapy in patients with advanced solid tumors or B-cell lymphomas is currently underway (NCT01897571). Other clinical trials for epigenetic modulators such as DNMTis, HMTis, HDACis, and adoptive T cell therapy are included in Table 2.

CONCLUSION

The advent of immunotherapy has changed the treatment options in NSCLC. Prior to immunotherapy and targeted agents, chemotherapy was the backbone of treatment. Currently, the first line standard treatment for stage IV NSCLC is anti–PD-1 with or without chemotherapy, with the addition of chemotherapy depending on the PD-L1 expressions of the patients (Mok et al., 2019). There is also the option of anti–PD-L1 and VEGFR inhibitor with chemotherapy in first line non-squamous NSCLC (Socinski et al., 2018). Recently, front-line nivolumab with ipilimumab in combination with short course chemotherapy showed overall survival benefit in patients with NSCLC and received U.S. Food and Drug Administration approval (Arenas-Ramirez et al., 2018). Unprecedented results of survival gain in NSCLC have accelerated scientists and clinicians to explore various combinations of immunotherapy with other agents in order to overcome acquired resistance. Indeed, elucidating the mechanisms underlying acquired resistance is necessary to provide treatment options for this subset of patients. Notably, the upregulation IFN-γ pathway, co-inhibition of immune checkpoints such as TIGIT, and inhibition of TGF-β have gained attention as promising potential therapeutic strategies and are awaiting results.

Article information

Mol. Cells.May 31, 2021; 44(5): 363-373.
Published online 2021-05-17. doi:  10.14348/molcells.2021.0044
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
2Division of Hemato-Oncology, Wonju Severance Christian Hospital, Yonsei University College of Medicine, Wonju 26426, Korea
3Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul 03722, Korea
*Correspondence: nobelg@yuhs.ac (HRK); sjha@yonsei.ac.kr (SJH)
Received February 25, 2021; Accepted March 23, 2021.
Articles from Mol. Cells are provided here courtesy of Mol. Cells

References

  • Abiko, K., Matsumura, N., Hamanishi, J., Horikawa, N., Murakami, R., Yamaguchi, K., Yoshioka, Y., Baba, T., Konishi, I., and Mandai, M. (2015). IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br. J. Cancer. 112, 1501-1509.
  • Alfaro, C., Teijeira, A., Oñate, C., Pérez, G., Sanmamed, M.F., Andueza, M.P., Alignani, D., Labiano, S., Azpilikueta, A., and Rodriguez-Paulete, A. (2016). Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin. Cancer Res.. 22, 3924-3936.
  • Arenas-Ramirez, N., Sahin, D., and Boyman, O. (2018). Epigenetic mechanisms of tumor resistance to immunotherapy. Cell. Mol. Life Sci.. 75, 4163-4176.
  • Arlauckas, S.P., Garris, C.S., Kohler, R.H., Kitaoka, M., Cuccarese, M.F., Yang, K.S., Miller, M.A., Carlson, J.C., Freeman, G.J., and Anthony, R.M. (2017). In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci. Transl. Med.. 9, eaal3604.
  • Ashizawa, T., Iizuka, A., Maeda, C., Tanaka, E., Kondou, R., Miyata, H., Sugino, T., Kawata, T., Deguchi, S., and Mitsuya, K. (2019). Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status. Immunol. Lett.. 216, 43-50.
  • Bach, E.A., Aguet, M., and Schreiber, R.D. (1997). The IFNγ receptor: a paradigm for cytokine receptor signaling. Annu. Rev. Immunol.. 15, 563-591.
  • Bagchi, S., Yuan, R., and Engleman, E.G. (2021). Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu. Rev. Pathol.. 16, 223-249.
  • Baxter, E., Windloch, K., Gannon, F., and Lee, J.S. (2014). Epigenetic regulation in cancer progression. Cell Biosci.. 4, 45.
  • Chanmee, T., Ontong, P., Konno, K., and Itano, N. (2014). Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 6, 1670-1690.
  • Chauvin, J.M., Pagliano, O., Fourcade, J., Sun, Z., Wang, H., Sander, C., Kirkwood, J.M., Chen, T.H., Maurer, M., and Korman, A.J. (2015). TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest.. 125, 2046-2058.
  • Chen, P.L., Roh, W., Reuben, A., Cooper, Z.A., Spencer, C.N., Prieto, P.A., Miller, J.P., Bassett, R.L., Gopalakrishnan, V., and Wani, K. (2016). Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov.. 6, 827-837.
  • Ettinger, D.S., Wood, D.E., Aggarwal, C., Aisner, D.L., Akerley, W., Bauman, J.R., Bharat, A., Bruno, D.S., Chang, J.Y., and Chirieac, L.R. (2019). NCCN guidelines insights: non-small cell lung cancer, version 1.2020: featured updates to the NCCN guidelines. J. Natl. Compr. Canc. Netw.. 17, 1464-1472.
  • Fong, L., Forde, P.M., Powderly, J.D., Goldman, J.W., Nemunaitis, J.J., Luke, J.J., Hellmann, M.D., Kummar, S., Doebele, R.C., and Mahadevan, D. (2017). Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients. J. Clin. Oncol.. 35, 3004.
  • Galon, J. and Bruni, D. (2019). Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov.. 18, 197-218.
  • Garcia-Diaz, A., Shin, D.S., Moreno, B.H., Saco, J., Escuin-Ordinas, H., Rodriguez, G.A., Zaretsky, J.M., Sun, L., Hugo, W., and Wang, X. (2017). Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep.. 19, 1189-1201.
  • Genova, C., Boccardo, S., Mora, M., Rijavec, E., Biello, F., Rossi, G., Tagliamento, M., Dal Bello, M.G., Coco, S., and Alama, A. (2019). Correlation between B7-H4 and survival of non-small-cell lung cancer patients treated with nivolumab. J. Clin. Med.. 8, 1566.
  • Gettinger, S., Choi, J., Hastings, K., Truini, A., Datar, I., Sowell, R., Wurtz, A., Dong, W., Cai, G., and Melnick, M.A. (2017). Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov.. 7, 1420-1435.
  • Hanks, B.A., Holtzhausen, A., Evans, K., Heid, M., and Blobe, G.C. (2014). Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma. J. Clin. Oncol.. 32, 3011.
  • Hellmann, M.D., Friedman, C.F., and Wolchok, J.D. (2016). Combinatorial cancer immunotherapies. Adv. Immunol.. 130, 251-277.
  • Hou, A., Hou, K., Huang, Q., Lei, Y., and Chen, W. (2020). Targeting myeloid-derived suppressor cell, a promising strategy to overcome resistance to immune checkpoint inhibitors. Front. Immunol.. 11, 783.
  • Hu-Lieskovan, S. and Ribas, A. (2017). New combination strategies using PD-1/L1 checkpoint inhibitors as a backbone. Cancer J.. 23, 10-22.
  • Jenkins, R.W., Barbie, D.A., and Flaherty, K.T. (2018). Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer. 118, 9-16.
  • Kanwal, R. and Gupta, S. (2012). Epigenetic modifications in cancer. Clin. Genet.. 81, 303-311.
  • Kim, D., Lee, Y.S., Kim, D.H., and Bae, S.C. (2020). Lung cancer staging and associated genetic and epigenetic events. Mol. Cells. 43, 1-9.
  • Koyama, S., Akbay, E.A., Li, Y.Y., Herter-Sprie, G.S., Buczkowski, K.A., Richards, W.G., Gandhi, L., Redig, A.J., Rodig, S.J., and Asahina, H. (2016). Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun.. 7, 10501.
  • Mahoney, K.M., Rennert, P.D., and Freeman, G.J. (2015). Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov.. 14, 561-584.
  • Manguso, R.T., Pope, H.W., Zimmer, M.D., Brown, F.D., Yates, K.B., Miller, B.C., Collins, N.B., Bi, K., LaFleur, M.W., and Juneja, V.R. (2017). In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 547, 413-418.
  • Mariathasan, S., Turley, S.J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel, E.E., III, Array, Koeppen, H., Astarita, J.L., and Cubas, R. (2018). TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 554, 544-548.
  • Mazzone, R., Zwergel, C., Mai, A., and Valente, S. (2017). Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin. Epigenetics. 9, 59.
  • Meder, L., Schuldt, P., Thelen, M., Schmitt, A., Dietlein, F., Klein, S., Borchmann, S., Wennhold, K., Vlasic, I., and Oberbeck, S. (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res.. 78, 4270-4281.
  • Meyer, C., Cagnon, L., Costa-Nunes, C.M., Baumgaertner, P., Montandon, N., Leyvraz, L., Michielin, O., Romano, E., and Speiser, D.E. (2014). Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol. Immunother.. 63, 247-257.
  • Miao, D., Margolis, C.A., Gao, W., Voss, M.H., Li, W., Martini, D.J., Norton, C., Bossé, D., Wankowicz, S.M., and Cullen, D. (2018). Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 359, 801-806.
  • Mok, T.S.K., Wu, Y.L., Kudaba, I., Kowalski, D.M., Cho, B.C., Turna, H.Z., Castro, G., Srimuninnimit, V., Laktionov, K.K., and Bondarenko, I. (2019). Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 393, 1819-1830.
  • Neel, J.C., Humbert, L., and Lebrun, J.J. (2012). The dual role of TGFβ in human cancer: from tumor suppression to cancer metastasis. ISRN Mol. Biol.. 2012, 381428.
  • Pan, D., Kobayashi, A., Jiang, P., Ferrari, , de Andrade, L., Tay, R.E., Luoma, A.M., Tsoucas, D., Qiu, X., Lim, K., and Rao, P. (2018). A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 359, 770-775.
  • Pauken, K.E., Sammons, M.A., Odorizzi, P.M., Manne, S., Godec, J., Khan, O., Drake, A.M., Chen, Z., Sen, D.R., and Kurachi, M. (2016). Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 354, 1160-1165.
  • Peng, W., Chen, J.Q., Liu, C., Malu, S., Creasy, C., Tetzlaff, M.T., Xu, C., McKenzie, J.A., Zhang, C., and Liang, X. (2016). Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov.. 6, 202-216.
  • Pereira, C., Gimenez-Xavier, P., Pros, E., Pajares, M.J., Moro, M., Gomez, A., Navarro, A., Condom, E., Moran, S., and Gomez-Lopez, G. (2017). Genomic profiling of patient-derived xenografts for lung cancer identifies B2M inactivation impairing immunorecognition. Clin. Cancer Res.. 23, 3203-3213.
  • Platten, M., von Knebel Doeberitz, N., Oezen, I., Wick, W., and Ochs, K. (2015). Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front. Immunol.. 5, 673.
  • Pourmir, I., Gazeau, B., de Saint Basile, H., and Fabre, E. (2020). Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer: myth or reality?. Cancer Drug Resist.. 3, 276-286.
  • Remon, J., Passiglia, F., Ahn, M.J., Barlesi, F., Forde, P.M., Garon, E.B., Gettinger, S., Goldberg, S.B., Herbst, R.S., and Horn, L. (2020). Immune checkpoint inhibitors in thoracic malignancies: review of the existing evidence by an IASLC expert panel and recommendations. J. Thorac. Oncol.. 15, 914-947.
  • Ren, D., Hua, Y., Yu, B., Ye, X., He, Z., Li, C., Wang, J., Mo, Y., Wei, X., and Chen, Y. (2020). Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. Mol. Cancer. 19, 19.
  • Ribas, A., Shin, D.S., Zaretsky, J., Frederiksen, J., Cornish, A., Avramis, E., Seja, E., Kivork, C., Siebert, J., and Kaplan-Lefko, P. (2016). PD-1 blockade expands intratumoral memory T cells. Cancer Immunol. Res.. 4, 194-203.
  • Ricciuti, B., Leonardi, G.C., Puccetti, P., Fallarino, F., Bianconi, V., Sahebkar, A., Baglivo, S., Chiari, R., and Pirro, M. (2019). Targeting indoleamine-2, 3-dioxygenase in cancer: scientific rationale and clinical evidence. Pharmacol. Ther.. 196, 105-116.
  • Rodriguez-Abreu, D., Johnson, M.L., Hussein, M.A., Cobo, M., Patel, A.J., Secen, N.M., Lee, K.H., Massuti, B., Hiret, S., and Yang, J.C.H. (2020). Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J. Clin. Oncol.. 38, 9503.
  • Sakaguchi, S., Yamaguchi, T., Nomura, T., and Ono, M. (2008). Regulatory T cells and immune tolerance. Cell. 133, 775-787.
  • Saleh, R. and Elkord, E. (2019). Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett.. 457, 168-179.
  • Sharma, P., Hu-Lieskovan, S., Wargo, J.A., and Ribas, A. (2017). Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 168, 707-723.
  • Shin, D.S., Zaretsky, J.M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C.S., Hugo, W., Sandoval, S., and Torrejon, D.Y. (2017). Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov.. 7, 188-201.
  • Socinski, M.A., Jotte, R.M., Cappuzzo, F., Orlandi, F., Stroyakovskiy, D., Nogami, N., Rodríguez-Abreu, D., Moro-Sibilot, D., Thomas, C.A., and Barlesi, F. (2018). Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med.. 378, 2288-2301.
  • Spranger, S., Koblish, H.K., Horton, B., Scherle, P.A., Newton, R., and Gajewski, T.F. (2014). Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J. Immunother. Cancer. 2, 3.
  • Stanley, E.R. and Chitu, V. (2014). CSF-1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol.. 6, a021857.
  • Steven, A., Fisher, S.A., and Robinson, B.W. (2016). Immunotherapy for lung cancer. Respirology. 21, 821-833.
  • Su, T., Zhang, Y., Valerie, K., Wang, X.Y., Lin, S., and Zhu, G. (2019). STING activation in cancer immunotherapy. Theranostics. 9, 7759-7771.
  • Sucker, A., Zhao, F., Pieper, N., Heeke, C., Maltaner, R., Stadtler, N., Real, B., Bielefeld, N., Howe, S., and Weide, B. (2017). Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat. Commun.. 8, 15440.
  • Sucker, A., Zhao, F., Real, B., Heeke, C., Bielefeld, N., Maβen, S., Horn, S., Moll, I., Maltaner, R., and Horn, P.A. (2014). Genetic evolution of T-cell resistance in the course of melanoma progression. Clin. Cancer Res.. 20, 6593-6604.
  • Taube, J.M., Anders, R.A., Young, G.D., Xu, H., Sharma, R., McMiller, T.L., Chen, S., Klein, A.P., Pardoll, D.M., and Topalian, S.L. (2012). Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med.. 4, 127ra37.
  • Thommen, D.S., Schreiner, J., Müller, P., Herzig, P., Roller, A., Belousov, A., Umana, P., Pisa, P., Klein, C., and Bacac, M. (2015). Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol. Res.. 3, 1344-1355.
  • Toor, S.M., Nair, V.S., Decock, J., and Elkord, E. (2020). Immune checkpoints in the tumor microenvironment. Semin. Cancer Biol.. 65, 1-12.
  • Topalian, S.L., Drake, C.G., and Pardoll, D.M. (2015). Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 27, 450-461.
  • Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., Pinton, S., Zhang, J., Kalathur, M., and Civenni, G. (2014). Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep.. 9, 75-89.
  • Vanpouille-Box, C., Diamond, J.M., Pilones, K.A., Zavadil, J., Babb, J.S., Formenti, S.C., Barcellos-Hoff, M.H., and Demaria, S. (2015). TGFβ is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res.. 75, 2232-2242.
  • Vijayan, D., Young, A., Teng, M.W., and Smyth, M.J. (2017). Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer. 17, 709-724.
  • Voron, T., Colussi, O., Marcheteau, E., Pernot, S., Nizard, M., Pointet, A.L., Latreche, S., Bergaya, S., Benhamouda, N., and Tanchot, C. (2015). VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med.. 212, 139-148.
  • Wang, F., Wang, S., and Zhou, Q. (2020). The resistance mechanisms of lung cancer immunotherapy. Front. Oncol.. 10, 568059.
  • Xu, L.J., Ma, Q., Zhu, J., Li, J., Xue, B.X., Gao, J., Sun, C.Y., Zang, Y.C., Zhou, Y.B., and Yang, D.R. (2018). Combined inhibition of JAK1, 2/Stat3-PD-L1 signaling pathway suppresses the immune escape of castration-resistant prostate cancer to NK cells in hypoxia. Mol. Med. Rep.. 17, 8111-8120.
  • Yamaguchi, H. and Hung, M.C. (2014). Regulation and role of EZH2 in cancer. Cancer Res. Treat.. 46, 209-222.
  • Young, A., Ngiow, S.F., Gao, Y., Patch, A.M., Barkauskas, D.S., Messaoudene, M., Lin, G., Coudert, J.D., Stannard, K.A., and Zitvogel, L. (2018). A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res.. 78, 1003-1016.
  • Yuen, K.C., Liu, L.F., Gupta, V., Madireddi, S., Keerthivasan, S., Li, C., Rishipathak, D., Williams, P., Kadel, E.E., and Koeppen, H. (2020). High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat. Med.. 26, 693-698.
  • Zang, X., Loke, P., Kim, J., Murphy, K., Waitz, R., and Allison, J.P. (2003). B7x: a widely expressed B7 family member that inhibits t cell activation. Proc. Natl. Acad. Sci. U. S. A.. 100, 10388-10392.
  • Zaretsky, J.M., Garcia-Diaz, A., Shin, D.S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D.Y., Abril-Rodriguez, G., Sandoval, S., and Barthly, L. (2016). Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med.. 375, 819-829.
  • Zauderer, M.G., Szlosarek, P.W., Le Moulec, S., Popat, S., Taylor, P., Planchard, D., Scherpereel, A., Jahan, T.M., Koczywas, M., and Forster, M. (2020). Safety and efficacy of tazemetostat, an enhancer of zeste-homolog 2 inhibitor, in patients with relapsed or refractory malignant mesothelioma. J. Clin. Oncol.. 38, 9058.
  • Zhang, H., Conrad, D.M., Butler, J.J., Zhao, C., Blay, J., and Hoskin, D.W. (2004). Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3′, 5′-monophosphate and phosphatases. J. Immunol.. 173, 932-944.
  • Zhu, Y., Knolhoff, B.L., Meyer, M.A., Nywening, T.M., West, B.L., Luo, J., Wang-Gillam, A., Goedegebuure, S.P., Linehan, D.C., and DeNardo, D.G. (2014). CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res.. 74, 5057-5069.
  • Zingg, D., Arenas-Ramirez, N., Sahin, D., Rosalia, R.A., Antunes, A.T., Haeusel, J., Sommer, L., and Boyman, O. (2017). The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep.. 20, 854-867.

Figure 1

Immune suppressive and immune stimulatory cell-favored niche.
The immune suppressive environment (left) shows the 1) immune suppressive cells including Tregs and MDSCs, 2) the expression of immune suppressive cytokines, and 3) upregulation of immune checkpoint receptors such as TIGIT, LAG-3, and TIM-3 by T cells. The immune stimulatory environment includes PD-1 expression by T cells (right). The immune suppressive cell-favored niche does not respond well to ICIs, while the immune stimulatory responds favorably to ICIs.

Table 1

Mechanisms of acquired resistance and potential therapeutic approaches

Resistance mechanisms Description of resistance mechanisms Potential therapeutic approaches
Loss of immunogenic neoantigen Defects in IFN-γ pathway STING agonist, JAK inhibitor, STAT inhibitor
Upregulation of alternate immune checkpoint receptors Compensatory upregulation of inhibitory receptors (LAG-3, TIM-3, TIGIT, BTLA, VISTA, SIGLEC9) Blockade of alternate coinhibitory immune checkpoint receptors: LAG-3, TIM-3, TIGIT, BTLA, VISTA, SIGLEC9
Immune stimulatory agents: OX40, ICOS
Immunosuppressive cells and immunoregulative molecules in tumor microenvironment Increased immunosuppressive cells (Treg, MDSC, M2 macrophage) CSF1R inhibitor, TGF-β inhibitor
Elevated immunosuppressive cytokines (TGF-β, VEGF, IL-6/8) TGF-β inhibitor, VEGF inhibitor, IL-1β inhibitor, IL-6/8 inhibitor
Immunoregulative molecules: adenosine pathway, IDO1, B7-H4 A2AR inhibitor/anti-CD73, IDO inhibitor, B7-H4 inhibitor
Epigenetic modification Tumor suppressor, apoptosis gene modification Stability of chromatin remodeling complexes Epigenetic modulators: DNMTi, HMTi, HDACi Adoptive T cell therapy

Table 2

Clinical trials of investigational agents on acquired resistance

Mechanism Target Mechanism Drug Clinical trial No. Phase Tumor types Treatment arms Status
INF-γ pathway STING STING agonist E7766 NCT04144140 1 Solid tumor, lymphoma E7766 Recruiting
GSK3745417 NCT03843359 1 Solid tumor GSK3745417 ± pembrolizumab Recruiting
MIW815 NCT03172936 1 Solid tumor, lymphoma MIW815 + PDR001 Active, not recruiting
SNX281 NCT04609579 1 Solid tumor, lymphoma SNX281 ± pembrolizumab Recruiting
TAK-676 NCT04420884 1 Solid tumor TAK-676 ± pembrolizumab Recruiting
JAK JAK1 inhibitor AZD4205 NCT03450330 1,2 NSCLC AZD4205 + osimertinib Completed
Itacitinib (INCB039110) NCT03425006 2 NSCLC Itacitinib + pembrolizumab Active, not recruiting
JAK1/2 inhibitor Ruxolitinib (INCB018424) NCT02145637 1 NSCLC Ruxolitinib + afatinib Completed
STAT STAT3 inhibitor TTI-101 NCT03195699 1 Solid tumor TTI-101 Recruiting
SHP-1 agonist SC-43 NCT04733521 1,2 NSCLC, biliary tract cancer SC-43 + cisplatin Not yet recruiting
Blockade of alternate coinhibitory immune checkpoint receptors LAG-3 LAG-3 fusion protein Eftilagimod alpha (IMP321) NCT03625323 2 NSCLC, HNSCC Eftilagimodalpha + pembrolizumab Recruiting
IgG4 mAb Relatlimab (BMS-986016) NCT02750514 2 NSCLC Nivolumab ± relatlimab or ipilimumab or BMS-986205 or dasatinib Active, not recruiting
IgG4 mAb LAG525 NCT02460224 1,2 Solid tumor LAG525 ± spartalizumab (PDR001) Active, not recruiting
mAb BI 754111 NCT03780725 1 NSCLC, HNSCC BI 754111 + BI 754091 Completed
IgG4 mAb Mavezelimab (MK-4280) NCT03516981 2 NSCLC Pembrolizumab + quavonlimab or MK-4280 or lenvatinib Recruiting
TIM-3 Anti-PD-1/TIM-3 bispecific Ab RO7121661 NCT03708328 1 Solid tumor RO7121661 Recruiting
Anti-TIM-3 mAb INCAGN02390 NCT03652077 1 Solid tumor INCAGN02390 Active, not recruiting
Sym023 NCT03489343 1 Solid tumor, lymphoma Sym023 Completed
LY3321367 NCT03099109 1 Solid tumor LY3300054 (anti-PD-L1), LY3321367, LY3300054 + LY3321367 Active, not recruiting
Cobolimab (TSR-022) NCT02817633 1 Solid tumor Cobolimab ± nivolumab, cobolimab + TSR-042 ± TSR-033 or docetaxel Recruiting
Sabatolimab (MBG453) NCT02608268 1,2 Solid tumor Sabatolimab ± PDR001 or decitabine Active, not recruiting
TIGIT Anti-TIGIT mAb Tiragolumab (MTIG7192A/RG-6058) NCT04294810 3 NSCLC Atezolizumab ± tiragolumab Recruiting
NCT04256421 3 SCLC Atezolizumab + carboplatin + etoposide ± tiragolumab Recruiting
Vibostolimab (MK-7684) NCT02964013 1 Solid tumor Vibostolimab ± pembrolizumab ± pemetrexed/carboplatin, vibostolimab + carboplatin + cisplatin + etoposide Recruiting
BMS-986207 NCT02913313 1,2 Solid tumor BMS-986207 ± nivolumab Active, not recruiting
Domvanalimab (AB-154) NCT04262856 2 NSCLC Zimberelimab ± dombvanalimab ± etrumadenant Recruiting
IBI939 NCT04672356 1 NSCLC, SCLC IBI939 + sintilimab Not yet recruiting
BTLA Anti-OX40 mAb Cudarolimab (IBI101) NCT03758001 1 Solid tumor Cudarolimab ± sintilimab Recruiting
Anti-BTLA mAb TAB004 NCT04137900 1 Solid tumor TAB004 Recruiting
VISTA Anti-VISTA mAb JNJ-61610588 NCT02671955 1 Solid tumor JNJ-61610588 Terminated
CI-8993 NCT04475523 1 Solid tumor CI-8993 Recruiting
Small molecule targeting VISTA and PD-L1 CA-170 NCT02812875 1 Solid tumor, lymphoma CA-170 Completed
Immune stimulatory agents OX40 Hexavalent OX40 agonist Ab INBRX-106 NCT04198766 1 Solid tumor INBRX-106 ± pembrolizumab Recruiting
PD1-Fc-OX40L SL-279252 NCT03894618 1 Solid tumor, lymphoma SL-279252 Recruiting
Anti-OX40 agonist mAb PF-04518600 NCT02315066 1 Solid cancer PF-04518600 ± PF-05082566 Completed
INCAGN01949 NCT02923349 1,2 Solid tumor INCAGN01949 Completed
ICOS Anti-ICOS mAb GSK3359609 NCT03693612 2 Solid tumor GSK3359609 + tremelimumab, docetaxel + paclitaxel + cetuximab Recruiting
JTX-2011 NCT02904226 1,2 Solid tumor JTX-2011 + pembrolizumab or nivolumab or ipilimumab Completed
KY1044 NCT03829501 1,2 Solid tumor KY1044 ± atezolizumab Completed
Tumor microenvironment CSF1R MET, CSF1R, SRC kinase inhibitor TPX-0022 NCT03993873 1 Solid tumor TPX-0022 Recruiting
CSF1R mAb Cabiralizumab (FPA008) NCT02526017 1 Solid tumor FPA008 + BMS-936558 Completed
TGF-b TGF-bR inhibitor Galunisertib (LY2157299) NCT02423343 1,2 Solid tumor Galunisertib + nivolumab Completed
TEW 7197 NCT02160106 1 Solid tumor TEW-7197 Completed
TGF-b inhibitor AVID200 NCT03834662 1 Solid tumor AVID200 Active, not recruiting
Anti-TGF-bmAb SAR-439459 NCT04729725 1 Solid tumor SAR-439459 + cemiplimab Not yet recruiting
VEGF VEGFR TKI inhibitor Vandetanib (ZD6474) NCT00418886 3 NSCLC Vandetanib + pemetrexed Active, not recruiting
Axitinib (AG-013736) NCT03472560 2 NSCLC, urothelial cancer Axitinib + avelumab Active, not recruiting
Apatinib (YN968D1) NCT03389256 2 EGFR T790M-negative NSCLC Apatinib + EGFR-TKI Not yet recruiting
Anti-VEGF mAb Bevacizumab (L01XC07) NCT00451906 3 NSCLC Bevacizumab + first-line chemotherapy Completed
IBI305 NCT03802240 3 Non-squamous NSCLC Sintilimab ± IBI305 + pemetrexed + cisplatin Recruiting
Anti-VEGFR mAb Ramucirumab (LY3009806) NCT04340882 2 NSCLC Ramucirumab + docetaxel + pembrolizumab Recruiting
Aurora B/VEGFR/PDGFR/c-Kit/CSF1R inhibitor Chiauranib (CS2164) NCT03216343 1 SCLC Chiauranib Recruiting
IL-1b Anti-IL-1b mAb Canakinumab (ACZ885) NCT03626545 3 NSCLC Canakinumab + docetaxel Active, not recruiting
IL1RAP Ab CAN04 NCT04452214 1 Solid tumor CAN04 + pembrolizumab Recruiting
IL-6 Anti-IL-6R mAb Tocilizumab (RO4877533) NCT04691817 1,2 NSCLC Tocilizumab + atezolizumab Not yet recruiting
Anti-IL-6 mAb Siltuximab (CNTO 328) NCT00841191 1,2 Solid tumor Siltuximab Completed
IL-8 Anti-IL-8 mAb BMS-986253 NCT04123379 2 NSCLC, HCC Nivolumab + BMS-813160 or BMS-986253 Recruiting
Tumor microenvironment A2AR A2AR antagonist PBF-509 NCT02403193 1,2 NSCLC PBF-509 + PDR001 Active, not recruiting
Etrumadenant (AB928) NCT03846310 1 Lung cancer Etrumadenant + carboplatin + pemetrexed Recruiting
CD73 Small molecule CD73 inhibitor LY3475070 NCT04148937 1 Solid tumor LY3475070 ± pembrolizumab Recruiting
Anti-CD73 mAb CPI-006 NCT03454451 1 Solid cancer, NHL CPI-006 ± ciforadenant or pembrolizumab Recruiting
Oleclumab (MEDI9447) NCT03381274 1,2 EGFR-mutant NSCLC MEDI9447 + osimertinib or AZD4635 Active, not recruiting
Sym024 NCT04672434 1 Solid tumor Sym021 ± Sym024 Recruiting
NZV930 NCT03549000 1 Solid tumor NZV930 ± PDR001 ± NIR178 Recruiting
IDO1 IDO inhibitor Indoximod (NLG-8189) NCT02460367 1 NSCLC Indoximod + docetaxel + tergenpumatucel-L Active, not recruiting
B7-H4 B7-H4 Ab FPA150 NCT03514121 1 Solid tumor FPA150 + pembrolizumab Active, not recruiting
Epigenetic modulators Hypomethylating agents DNMTi Guadecitabine (SGI-110) NCT03913455 2 SCLC Guadecitabine + carboplatin Active, not recruiting
Cytidine nucleoside analogue CC-486 NCT02546986 2 NSCLC Pembrolizumab ± CC-486 Active, not recruiting
Deoxycitidine analogue Aza-TdCyd NCT03366116 1 Solid tumor Aza-TdCyd Recruiting
HMTi EZH2 inhibitor Tazemetostat (EPZ-6438) NCT01897571 1,2 Solid tumor, B-cell lymphoma Tazemetostat Active, not recruiting
HDACi HDAC inhibitor ACY-241 NCT02635061 1 NSCLC ACY-241 + nivolumab Active, not recruiting
Mocetinostat (MGCD01013) NCT02954991 2 NSCLC Nivolumab + glesatinib or sitravatinib or mocetinostat Active, not recruiting
Entinostat (SNDX-275) NCT01928576 2 NSCLC Entinostat + azacitidine + nivolumab Recruiting
Vorinostat (MK0683) NCT02638090 1,2 NSCLC Pembrolizumab ± vorinostat Recruiting
Abexinostat (PCI-24781) NCT03590054 1 Solid tumor Abexinostat + pembrolizumab Recruiting
Adoptive T cell therapy Genetically modified T cells NCT02408016 1,2 NSCLC, mesothelioma Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes Active, not recruiting
Genetically modified T cells NCT02706392 1 ROR1-positive Solid tumor ROR1 CAR-specific autologous T-Lymphocytes Recruiting