Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

Wilcox, Ryan A.; Flies, Dallas B.; Zhu, Gefeng; Johnson, Aaron J.; Tamada, Koji; Chapoval, Andrei I.; Strome, Scott E.; Pease, Larry R.; Chen, Lieping

doi:10.1172/jci14184

Cited by 145 publications

(144 citation statements)

References 42 publications

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“…Potential mechanisms of 4-1BB agonistic antibody-mediated tumor regressions include breaking of immunologic ignorance and prevention of T-cell deletion and anergy (5,35,36). Given that 4-1BB is specifically expressed on antigen-experienced T cells (7,37), the observed increase in 4-1BB þ T cells may implicate an enhanced immune response to tumor challenge in anti-4-1BB-treated animals.…”

Section: Discussionmentioning

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

229

164

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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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Section: Discussionmentioning

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

229

164

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“…15 4-1BB mediates signaling either by ligation with natural ligand expressed on activated APC or experimentally by binding an anti-4-1BB agonistic antibody. We previously developed a recombinant adenovirus expressing membrane-bound mouse 4-1BBL (ADV/4-1BBLm) consisting of the extracellular domain and the transmembrane domain of 4-1BBL.…”

Section: Discussionmentioning

confidence: 99%

The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

et al. 2005

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We have previously shown that the local-membrane bound 4-1BB ligand and IL-12 gene transfer induced a significant antitumor response in a mouse colon carcinoma model. However, a high viral dose was required in order to achieve the best efficacy. In this study, we hypothesize that the systemic administration of soluble Ig-4-1BB ligand can give rise to better T-cell immune activation than local gene delivery. With potential clinical applications in mind, we further compare whether the natural 4-1BB ligand fused to mouse IgG2a (Ig-4-1BBL) would be as effective as the agonistic anti-4-1BB antibody. The dimeric form of Ig-4-1BBL was purified from HeLa cells transduced with a recombinant adenovirus (ADV/ Ig-4-1BBL) expressing Ig-4-1BBL. Functional activity was confirmed by the ligand's ability to bind to activated splenic T cells or bone marrow (BM)-derived dendritic cells (DCs) that express 4-1BB receptor. The soluble Ig-4-1BBL efficiently costimulated CD3-activated T-cell proliferation in vitro. More importantly, it induced tumor-specific CTLs as effectively as the agonistic anti-4-1BB antibody. When combined with IL-12 gene transfer, systemic administration of the Ig-4-1BBL proved to be more potent than local gene delivery. In addition, the Ig-4-1BBL is as potent as the agonistic anti-4-1BB antibody for the treatment of hepatic MCA26 colon carcinoma, resulting in 50% complete tumor regression and long-term survival. In long-term surviving mice, both treatment modalities induced persistent tumor-specific CTL activity. In summary, these results suggest that the systemic delivery of Ig-4-1BBL can generate a better antitumor response than local gene delivery. Ig-4-1BBL had equivalent biological functions when compared to the agonistic anti-4-1BB antibody. Thus, soluble 4-1BBL dimmer can be developed as a promising agent for cancer therapy in humans. Gene Therapy (2005) 12, 1526-1533.

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“…C o n t r o l a n t i -4 -1 B B a n t i -C D 4 0 a n t i -4 -1 B B / a n t i -C D 4 0 a n t i -4 -1 B B / a n t i -0 X 4 0 a n t i -4 -1 B B / a n t i -C result in a small number of long-term survivors [29]. Mice received 1 Â 10 5 B16-F10 cells i.v.…”

Section: Combinations Of Immunostimulatory Mab Can Immunise Against Mmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

Cited by 145 publications

References 42 publications

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

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

The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

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