Antagonism of IAPs Enhances CAR T-cell Efficacy

Michie, Jessica; Beavis, Paul A.; Freeman, Andrew J.; Vervoort, Stephin J.; Ramsbottom, Kelly M.; Narasimhan, Vignesh; Lelliott, Emily J.; Lalaoui, Najoua; Ramsay, Robert G.; Johnstone, Ricky W.; Silke, John; Darcy, Phillip K.; Voskoboinik, Ilia; Kearney, Conor J.; Oliaro, Jane

doi:10.1158/2326-6066.cir-18-0428

Cited by 75 publications

(57 citation statements)

References 29 publications

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“…3). T cells are another source of TNFα 49 , which could explain why CAT-T cells synergize with an IAP antagonist to treat cancer 50 . In particular, IAP antagonists can augment human and mouse T cell responses and cytokine production to physiologically relevant stimuli 51,52 .…”

Section: Discussionmentioning

confidence: 99%

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Lei

Duan

et al. 2020

Sci Rep

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The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycinresistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy. Breast cancer (BC) accounts for nearly a quarter of all cancers in women worldwide. It is estimated that 268,600 women will be diagnosed with invasive BC in the US in 2019 and 41,760 will die from it 1. The most challenging issue for patients with BC is metastasis to other organs, including bone, lung, liver and brain; this causes about 90% of BC deaths. For decades, BC treatment has included surgery, radiation therapy (RT), chemotherapy (CT), and/or hormonal therapy. However, none of the current therapies effectively prevents or eliminates BC. Adjuvant CT benefits only a small proportion (5-10%) of patients 2. Similarly, RT has resulted in only a 5% reduction in the 15-year BC mortality rate 3. One reason for the poor therapeutic outcome could be that many patients already have micro-metastases when their primary cancers are diagnosed 4-6. Bone metastases are distinct from metastases to other organs because of cancer-associated osteolysis due to enhanced osteoclast (OC) formation and activity and associated release of cancer-promoting proteins from the resorbed bone matrix, including TGFβ 7,8. Current standard anti-resorptive drugs (bisphosphonates and the RANKL inhibitor, denosumab) inhibit bone resorption and reduce skeletal-related events (SREs) 9,10 , but they do not prolong patient survival, and 30-50% of BC patients on these drugs still develop new bone metastases 9,11,12. The development and progression of BC metastases depend on interactions between the cancer cells and the host organ microenvironment. For example, circulating cancer cells can be attracted to bone by osteoblasts (OBs) or their progenitors, mesenchymal stem cells (MSCs), by expression of proteins, such as integrins, chemokines, Notch, nestin, and osteopontin by these cells 12 , and also via interactions between RANKL on OBs/MSCs and RANK expressed by cancer cells 13,14. Cancer cells in turn promote OB/MSC production of more RANKL to enhance OC formation, causing osteolysis 1...

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Section: Discussionmentioning

confidence: 99%

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Lei

Duan

et al. 2020

Sci Rep

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“…And, as expected, given the important role TRAF2 plays in recruiting cIAPs and the synergistic effects of combining birinapant with ICIs in vitro shown by Kearney and colleagues, inhibition of cIAP1/2 by birinapant led to an even stronger response when combined with ICI drugs (anti-PD-1 therapy) [153]. Work showing that SMs can also synergize with Chimeric Antigen Receptor (CAR) T-cell therapy is discussed in an accompanying review in this series [73,154].…”

Section: Combination With Immunotherapymentioning

confidence: 71%

“…While TNF has pro-survival effects on melanoma cells, enhancing invasion and migration potential [70], SMs can convert this advantage to a liability. These results highlight that SMs may synergize with an inflammatory environment, whether induced or otherwise, to cause cancer cell death [71][72][73].…”

Section: Birinapantmentioning

confidence: 85%

Future Therapeutic Directions for Smac-Mimetics

Morrish

Brumatti

Silke

2020

Cells

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109

118

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It is well accepted that the ability of cancer cells to circumvent the cell death program that untransformed cells are subject to helps promote tumor growth. Strategies designed to reinstate the cell death program in cancer cells have therefore been investigated for decades. Overexpression of members of the Inhibitor of APoptosis (IAP) protein family is one possible mechanism hindering the death of cancer cells. To promote cell death, drugs that mimic natural IAP antagonists, such as second mitochondria-derived activator of caspases (Smac/DIABLO) were developed. Smac-Mimetics (SMs) have entered clinical trials for hematological and solid cancers, unfortunately with variable and limited results so far. This review explores the use of SMs for the treatment of cancer, their potential to synergize with up-coming treatments and, finally, discusses the challenges and optimism facing this strategy.

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“…Birinapant also significantly enhanced CAR T cell therapy, resulting in prolonged survival and tumour regression in tumour bearing mice, and significantly enhanced tumour cell death in a patient-derived tumoroid model, compared to CAR T cell or birinapant monotherapy [87]. Importantly, the ability of SMs to senstitise antigen negative cells to TNF-mediated apoptosis, an effect known as bystander killing (Figure 2), may be an effective strategy to avoid antigen negative relapse following CAR T cell therapy [88].…”

Section: Role Of Smac-mimetics In T Cell-specific Immunotherapiesmentioning

confidence: 95%

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Michie

Kearney

Hawkins

et al. 2020

Cells

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One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

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Antagonism of IAPs Enhances CAR T-cell Efficacy

Cited by 75 publications

References 29 publications

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Future Therapeutic Directions for Smac-Mimetics

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

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