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Immunotherapy has become a hotspot in cancer therapy in recent years. Several immune checkpoints inhibitors have been used to treat lung cancer. CD137 is a kind of costimulatory molecule that mediates T cell activation, which regulates the activity of immune cells in a variety of physiological and pathological processes. Targeting CD137 or its ligand (CD137L) has been studied, aiming to enhance anticancer immune responses. Accumulating studies show that anti‐CD137 mAbs alone or combined with other drugs have bright antitumor prospects. In the following, we reviewed the biology of CD137, the antitumor effects of anti‐CD137 Ab monotherapy and the combined therapy in lung cancer. Several studies in cells and animal models of lung cancer underscore the essential role of CD137 in cancer therapy. Anti‐CD137 Ab is a potent cancer immunotherapy drug, which can regulate the immune system by acting on a variety of cells in tumor microenvironment. The therapeutic effect of anti‐CD137 mAbs monotherapy in lung cancer is not satisfactory, especially in poorly immunogenic tumors. Combination therapies of anti‐CD137 mAbs with other reagents have shown great potentials of antitumor activities. The clinical potential and the side‐effects of anti‐CD137 mAbs in lung cancer should be determined by more clinical trials. In conclusion, anti‐CD137 mAbs is an attractive candidate for the immunotherapy of lung cancer.

The selective expression of CD137 on cells of the immune system (e.g., T and DC cells) and oncogenic cells in several types of cancer leads this molecule to be an attractive target to discover cancer immunotherapy. Therefore, specific antibodies against CD137 are being studied and developed aiming to activate and enhance anti-cancer immune responses as well as suppress oncogenic cells. Accumulating evidence suggests that anti-CD137 antibodies can be used separately to prevent tumor in some cases, while in other cases, these antibodies need to be co-administered with other antibodies or drugs/vaccines/regents for a better performance. Thus, in this work, we aim to update and discuss current knowledge about anti-cancer effects of anti-CD137 antibodies as mono- and combined-immunotherapies.

CD137, a member of the TNFR family, is a costimulatory receptor, and CD137L, a member of the TNF family, is its ligand. Studies using CD137- and CD137L-deficient mice and antibodies against CD137 and CD137L have revealed the diverse and paradoxical effects of these two proteins in various cancers, autoimmunity, infections, and inflammation. Both their cellular diversity and their spatiotemporal expression patterns indicate that they mediate complex immune responses. This intricacy is further enhanced by the bidirectional signal transduction events that occur when these two proteins interact in various types of immune cells. Here, we review the biology of murine CD137/CD137L, particularly, the complexity of their proximal signaling pathways, and speculate on their roles in immune responses.

Background Immune checkpoint inhibitors (ICIs), administered alone or combined with chemotherapy, are the standard of care in advanced non-oncogene addicted Non-Small Cell Lung Cancer (NSCLC). Despite these treatments' success, most long-term survival benefit is restricted to approximately 20% of patients, highlighting the need to identify novel biomarkers to optimize treatment strategies. In several solid tumors, immune soluble factors, the activatory CD137 + Tcells, and the immunosuppressive cell subsets Tregs and MDSCs (PMN(Lox1 + )-MDSC and M-MDSCs) correlated with responses to ICIs and clinical outcomes thus becoming appealing predictive and prognostic factors. This study investigated the role of distinct CD137 + Tcell subsets, Tregs, MDSCs, and immune-soluble factors in NSCLC patients as possible biomarkers. Methods The levels of T cells, MDSCs and soluble factors were evaluated in 89 metastatic NSCLC patients who underwent ICIs as first- or second-line treatment. T cell analysis was performed by cytoflurimetry evaluating Tregs and different CD137 + Tcell subsets also combined with CD3 + , CD8 + , PD1 + , and Ki67 + markers. Circulating cytokines and immune checkpoints were also evaluated by Luminex analysis. All these parameters were correlated with several clinical factors (age, sex, smoking status, PS and TPS), response to therapy, PFS , and OS . The analyses were conducted in the overall population and in patients treated with ICIs as first-line (naïve patients). Results In both groups of patients, high levels of circulating CD137 + and CD137 + PD1 + T cells (total, CD4 and CD8) and the soluble factor LAG3 positively correlated with response to therapy. In naïve patients, PMN(Lox1 + )-MDSCs negatively correlated with clinical response, and a high percentage of Tregs was associated with favorable survival. Moreover, the balance between Treg/CD137 + Tcells or PMN(Lox1 + )-MDSC/CD137 + Tcells was higher in non-responding patients and was associated with poor survival. CD137 + Tcells and Tregs resulted as two positive independent prognostic factors. Conclusion High levels of CD137 + , CD137 + PD1 + Tcells and sLAG3 could predict the response to ICIs in NSCLC patients independently by previous therapy. Combining the evaluation of CD137 + Tcells and Tregs also as Treg/CD137 + T cells ratio it is possible to identify naive patients with longer survival.

Negative immune regulation plays a notable role in tumor immunity. This study aimed to confirm that CD137 mediates negative immunoregulation as well as agonist activity in tumor immunity. Soluble CD137 (sCD137), a prominent splice variant of membrane-bound CD137 (mCD137), was identified, and its concentration in the blood of lung cancer patients was increased. The baseline concentration of sCD137 in the blood was negatively correlated with the efficacy of neoadjuvant immunochemotherapy in a pilot study. The percentage of CD137+ regulatory T cells (Tregs) in the blood of lung cancer patients was also increased, and further enriched at the tumor site; Foxp3, CTLA-4, IL-10, IL-35-Ebi3, sCD137 and costimulatory molecules expression were also higher, indicating increased immunosuppressive activity. A high percentage of CD137+ Tregs in the tumor was associated with worse OS outcomes among patients with high CD137+CD8+ T cell infiltration levels. Notably, targeting CD137+ Tregs using an engineered CD137 agonist with wild-type mouse IgG2a Fc clearly decreased the total Treg numbers and eliminated the tumor in the CT26 model and prolonged the survival rate of a Lewis lung carcinoma (LLC) model. These results indicated it may be possible to empower CD137 agonist with ability to abolish CD137-mediated negative regulation to enhance its antitumor efficacy.

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.

Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation–related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor–dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.

CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.

Costimulatory receptors on immune cells represent attractive targets for immunotherapy given that these molecules can increase the frequency of individual protective immune cell populations and their longevity, as well as enhance various effector functions. 4-1BB, a member of the TNF receptor superfamily, also known as CD137 and TNFRSF9, is one such molecule that is inducible on several cell types, including T cells and NK cells. Preclinical studies in animal models have validated the notion that stimulating 4-1BB with agonist reagents or its natural ligand could be useful to augment conventional T cell and NK cell immunity to protect against tumor growth and against viral infection. Additionally, stimulating 4-1BB can enhance regulatory T cell function and might be useful in the right context for suppressing autoimmunity. Two human agonist antibodies to 4-1BB have been produced and tested in clinical trials for cancer, with variable results, leading to the production of a wealth of second-generation antibody constructs, including bi- and multi-specifics, with the hope of optimizing activity and selectivity. Here, we review the progress to date in agonism of 4-1BB, discuss the complications in targeting the immune system appropriately to elicit the desired activity, together with challenges in engineering agonists, and highlight the untapped potential of manipulating this molecule in infectious disease and autoimmunity.

Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 andCD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.