Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAF<sup>V600E</sup>-PTEN-/- transgenic model of melanoma.

Hanks, Brent A.; Holtzhausen, Alisha; Evans, Kathy S.; Heid, Michelle E.; Blobe, Gerard C.

doi:10.1200/jco.2014.32.15_suppl.3011

Cited by 30 publications

(26 citation statements)

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“…Increased level of TGFβ is associated with poor prognosis in multiple different tumor types (Lin and Zhao, 2015; Massague, 2008). Preclinical models have shown synergy combining TGF-β receptor kinase inhibitor I with anti-CTLA-4 and inhibited tumor growth in a melanoma model (BRAF V600E PTEN −/− ) (Hanks et al, 2014) or fractionated radiation therapy by enhance T cell priming (Vanpouille-Box et al, 2015). Adenosine was shown to inhibit T cell proliferation and cytotoxic function via the A2A receptor on T cells (Zhang et al, 2004) as well as promote metastasis via the A2B receptor on tumor cells (Mittal et al, 2016).…”

Section: Tumor Cell-extrinsic Factors For Primary and Adaptive Resistmentioning

confidence: 99%

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Sharma

Hu‐Lieskovan

Wargo

et al. 2017

Cell

4,018

3,335

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Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are being elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

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Section: Tumor Cell-extrinsic Factors For Primary and Adaptive Resistmentioning

confidence: 99%

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Sharma

Hu‐Lieskovan

Wargo

et al. 2017

Cell

4,018

3,335

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“…This and other TGFβ inhibitors have been tested in combination therapy in preclinical models, showing synergy with other therapeutic modalities such as chemotherapy 165 and growth factor inhibition 166 . In a transgenic mouse melanoma model, galunisertib showed synergistic activity with anti-CTLA4 therapy 167 . A collaboration to study galunisertib in combination with nivolumab in advanced solid tumours has recently been announced by Bristol-Myers Squibb and Eli Lilly and Company.…”

Section: Killer Inhibitory Receptorsmentioning

confidence: 99%

Combination cancer immunotherapy and new immunomodulatory targets

Mahoney

Rennert²,

Freeman

2015

Nat Rev Drug Discov

1,124

907

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Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.

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“…Preclinically, combined treatment with a TFG-β receptor kinase inhibitor I and anti-CTLA-4 synergistically inhibited primary and metastatic tumor growth in a melanoma model (BRAF V600E PTEN −/− ) (170). The combination of the TFG-β receptor kinase inhibitor I (galunisertib) and anti-PD-L1 (durvalumab) or anti-PD-1 (nivolumab) are currently being clinically tested in patients with metastatic pancreatic cancer (NCT02734160, phase I) and NSCLC, hepatocellular carcinoma, or glioblastoma (NCT02423343, phase I/II).…”

Section: Combinations That Increase Tumor Killing (Step 7)mentioning

confidence: 99%

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

2016

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In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

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Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAF^V600E-PTEN-/- transgenic model of melanoma.

Cited by 30 publications

References 0 publications

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Combination cancer immunotherapy and new immunomodulatory targets

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

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Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma.

Cited by 30 publications

References 0 publications

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Combination cancer immunotherapy and new immunomodulatory targets

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

Contact Info

Product

Resources

About

Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAF^V600E-PTEN-/- transgenic model of melanoma.