Immunotherapy of Cancer with 4-1BB

Vinay, Dass S.; Kwon, Byoung S.

doi:10.1158/1535-7163.mct-11-0677

Cited by 162 publications

(131 citation statements)

References 74 publications

(106 reference statements)

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“…Among various TNFR family members including CD134 (OX-40), CD27, CD357 (GITR), and others, CD137 was the first identified as a possible immunotherapy target (26). The efficacy of its ligation was shown in different tumor studies, demonstrating that treatment of tumor-bearing mice with CD137 agonist therapy promoted effective antitumor immune responses (27). In this work, an anti-CD137 Ab that provides additional costimulatory signal to cells was used.…”

Section: Discussionmentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus–induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4+ T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8+ T cell–deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4+ T cells. Interestingly, a subset of CD4+Foxp3+ regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-α or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4+ T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3+CD4+ T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Akhmetzyanova

Zelinskyy

Littwitz-Salomon

et al. 2016

The Journal of Immunology

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“…The ligand that stimulates 4-1BB (4-1BBL) is expressed on antigen-presenting cells, including dendritic cells (DC), B cells, and macrophages (6). Ligation of 4-1BB receptors elicits a variety of immune cell-specific biologic responses.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, 4-1BB activation promotes cell proliferation, survival, and cytokine production in T cells. In several tumor models, 4-1BB agonists have demonstrated antitumor efficacy (6,7). Interestingly, in some autoimmunity models, 4-1BB agonist also inhibited autoimmune reactions partly by antagonizing Th17 cell polarization (8,9).…”

Section: Introductionmentioning

confidence: 99%

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Chen

Lee

Fisher

et al. 2015

Cancer Immunology Research

232

167

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Immunotherapies targeting the programmed death 1 (PD-1) coinhibitory receptor have shown great promise for a subset of patients with cancer. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of the anti-4-1BB/anti-PD-1 combination with that of the anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti-PD-1 and anti-4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of the anti-4-1BB/anti-PD-1 combination was dependent on IFNg and CD8 þ T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8 þ T cells by anti-4-1BB/anti-PD-1 cotreatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by the increased CD8 þ /Treg ratio and the enrichment of genes such as Cd3e, Cd8a, Ifng, and Eomes. In the spleen, the combination treatment shaped the immune system to an effector/memory phenotype and increased the overall activity of tumor-specific CD8 þ CTLs, reflecting a long-lasting systemic antitumor response. Furthermore, combination treatment in C57BL/6 mice showed no additional safety signals, and only minimally increased severity of the known toxicity relative to 4-1BB agonist alone. Therefore, in the absence of any cancer vaccine, anti-4-1BB/anti-PD-1 combination therapy is sufficient to elicit a robust antitumor effector/memory T-cell response in an aggressive tumor model and is therefore a candidate for combination trials in patients.

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“…The a-and b-chains from the MART-1 [26][27][28][29][30][31][32][33][34][35] -specific TCR termed F4 (or DMF4) 27,28 were subcloned into the pGEM-4Z/64A vector as described previously 28 and in vitro-transcribed mRNA for both TCR chains was introduced into human peripheral blood lymphocytes (PBLs) by electroporation as described previously. 28,29 Briefly, electroporation was performed at 400 V/500 lsec using an ElectroSquare Porator ECM 830 (BTX, San Diego, CA).…”

Section: Tcr and Peptidesmentioning

confidence: 99%

Enhanced antitumor activity mediated by human 4‐1BB‐engineered T cells

Daniel-Meshulam

Horovitz-Fried

Cohen

2013

Intl Journal of Cancer

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4-1BB (CD137) is a costimulatory molecule transiently expressed on the T-cell surface after TCR engagement, whereas its ligand 4-1BBL can be found on professional antigen-presenting cells, but more importantly, also on tumor cells. As the role of the 4-1BB/4-1BBL pathway has emerged central to CD81 T-cell responses and survival, we sought to test its relevance in the context of genetically modified human T cells. To that end, T cells purified from healthy donors and from vaccinatedmelanoma patients were transduced to express high levels of constitutive 4-1BB. 4-1BB-transduced T cells were cocultured with melanoma tumor lines and exhibited enhanced cytokine secretion, upregulation of activation markers as well as increased cytotoxicity in a chick-chorioallantoic membrane model of human melanoma tumors. In addition, these cells expanded and proliferated at a higher rate, expressed heightened levels of the antiapoptotic molecule Bcl XL and were also relatively insensitive to immunosuppression mediated by transforming growth factor-b, compared to control cells. We also show that 4-1BBL expression on the target cell is essential to 4-1BB-mediated functional improvement. Overall, we conclude that the modification of human T cells with 4-1BB yields enhanced antitumor function which may have important applications in therapies based on the genetic modification of patient lymphocytes.Costimulation actively shapes T-lymphocyte response as it can prevent the cells from entering a state of unresponsiveness or anergy. Costimulatory molecules are divided into two important families: the B7/CD28 and the tumor necrosis factors-receptor family.

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Immunotherapy of Cancer with 4-1BB

Cited by 162 publications

References 74 publications

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Enhanced antitumor activity mediated by human 4‐1BB‐engineered T cells

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