Twelve immunotherapy drugs that could cure cancers

Cheever, Martin A.

doi:10.1111/j.1600-065x.2008.00604.x

Cited by 307 publications

(234 citation statements)

References 129 publications

(155 reference statements)

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“…In 2007, The NCI Immunotherapy Agent Workshop ranked the PD-1/PD-L1 axis as the second most important immunotherapy target for pharmaceutical development (45). Confidence in the promise of PD-1/PD-L1-directed therapy has grown further with the registration of nivolumab and pembrolizumab, and following a number of reports of early stage clinical trials (27)(28)(29)(30)(31), in which responses to treatment were observed in patients with a number of other cancers, including renal cancer and NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

Stewart¹,

Morrow²,

Hammond³

et al. 2015

Cancer Immunology Research

349

255

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Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

Stewart¹,

Morrow²,

Hammond³

et al. 2015

Cancer Immunology Research

349

255

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“…Interleukin (IL)-15 and 4-1BB-directed agents have emerged here as promising candidates (3). IL-15 belongs to the cytokines of the common cytokine receptor g chain (gc) family (4).…”

Section: Introductionmentioning

confidence: 99%

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

Kermer

Hornig

Harder

et al. 2014

Molecular Cancer Therapeutics

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Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common g-chain (gc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Ra chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-g release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.

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“…In light of their immunostimulatory activity, TLR agonists are included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. 1,2 With the exception of Imiquimod, a synthetic TLR7 agonist topically applied to treat basal cell carcinoma, most TLR agonists used in clinical trials have been administered systemically, since this route was reported to effectively activate adaptive immunity. 3 However, innate immune responses triggered by TLR agonists include the activation of natural killer (NK) cells, macrophages, neutrophils, monocytes and dendritic cells, most of which must be activated locally, unlike cells of the adaptive immune response which can reach the antigen wherever they are activated.…”

Section: Introductionmentioning

confidence: 99%

“…4 Local delivery of TLR agonists has been explored for those cancers amenable to drug injection into the tumor sites, and studies have shown the superior antitumor effect of locoregional delivery of the TLR9 agonist CpG-ODN as compared to systemic administration in experimental and clinical cancers, such as ovarian and bladder cancers. 1,2,5,6 For lung tumors, repeated inhalation of TLR agonists represents a convenient and practical approach to induce frequent replenishment of innate immune effectors at the tumor site, avoiding toxic effects of systemic treatment. Our studies of aerosol delivery of CpG-ODN as a strategy for local administration of immunostimulators 7 showed that aerosolized CpG-ODN reached the bronchoalveolar space, locally activated an immune response without signs of toxicity, and was more efficacious than systemic administration against lung metastases of N202.1A mammary carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

et al. 2015

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The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases in C57BL/6 mice. Aerosolization of CpG-ODN with Poly(I:C) into the bronchoalveolar space reduced the presence of M2-associated arginase-and IL-10-secreting macrophages in tumor-bearing lungs and increased the antitumor activity of aerosolized CpG-ODN alone against B16 lung metastases without apparent signs of toxicity or injury of the bronchial-bronchiolar structures and alveolar walls. Moreover, CpG-ODN/Poly(I:C) aerosol combined with dacarbazine, a therapeutic agent used in patients with inoperable metastatic melanoma able to exert immunostimulatory effects, led to a significant increase in antitumor activity as compared to treatments with aerosolized CpG-ODN/Poly(I:C) or dacarbazine alone. This effect was related to an enhanced recruitment and cytotoxic activity of tumor-infiltrating NK cells in the lung. Our results point to aerosol delivery as a convenient approach for repeated applications of immunostimulants in patients with lung metastases to maintain a continuous local activation of innate immune cells while suppressing polarization of tumor-infiltrating macrophages to an M2 phenotype.

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Twelve immunotherapy drugs that could cure cancers

Cited by 307 publications

References 129 publications

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

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