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IAP antagonists induce anti-tumor immunity in multiple myeloma

Nature Medicine volume 22, pages 1411–1420 (2016)Cite this article

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Abstract

The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.

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Figure 1: Pre-clinical activity of LCL161 in MM.
Figure 2: Clinical activity of LCL161 in patients with MM.
Figure 3: LCL161 induces a type-I IFN response in myeloma cells that is required for its in vivo activity.
Figure 4: LCL161 activates MΦ and dendritic cells.
Figure 5: LCL161 treatment promotes MΦ recruitment and phagocytosis of tumor cells.
Figure 6: Adaptive immunity is dispensable for the initial response to LCL161, but combination with PD1 blockade is curative.

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Acknowledgements

We thank U. Jariwala, E. Slosberg and colleagues at Novartis for providing LCL161 and supporting the clinical trial. We are grateful to L. Rimsza for assistance with histological evaluation of splenocytes from LCL161 treated Vk*MYC mice and to F. Asimakopoulos for assistance with experimental design. We are indebted to M.S. Diamond (Washington University) for sharing IRF3/7null mice, to David Shealy from Centocor for donating the murine TNF blocking antibody and to P. Cohen (Mayo Clinic Arizona) for donating CD4, CD8 and NK1.1 blocking antibodies. M.C. was supported by research grants from the National Cancer Institute: CA190045 and CA186781.

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  1. Arianna Calcinotto

    Present address: Present address: Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.,

Authors and Affiliations

  1. Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA

    Marta Chesi, Noweeda N Mirza, Victoria M Garbitt, Meaghen E Sharik, Amylou C Dueck, Yan W Asmann, Heidi E Kosiorek, Arianna Calcinotto, Daniel L Riggs, Niamh Keane, Gregory J Ahmann, Kevin M Morrison, Rafael Fonseca, Craig B Reeder, A Keith Stewart & P Leif Bergsagel

  2. Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA

    Ilseyar Akhmetzyanova & David Fooksman

  3. Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA

    Martha Q Lacy, David Dingli, Shaji K Kumar, Angela Dispenzieri, Francis Buadi, Morie A Gertz & Yi Lin

  4. Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA

    Sikander Ailawadhi & Asher A Chanan-Khan

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Contributions

M.C. conceived the experiments. M.C., N.N.M., V.M.G., M.E.S., D.L.R. and N.K. executed the experiments. A.C.D. and H.E.K. provided statistical analysis of preclinical and clinical studies. Y.W.A. and P.L.B. performed bioinformatics analysis. A.C. contributed to the design of the study. G.J.A. processed clinical samples. K.M.M. coordinated patient accrual. R.F. supervised clinical sample processing and data acquisition. M.Q.L., D.D., S.K.K., S.A., A.D., F.B., M.A.G., C.B.R., Y.L., A.A.C.-K., A.K.S. and P.L.B. enrolled myeloma patients in the clinical trial. D.F. and I.A. designed and performed intra-vital microscopy studies. P.L.B. designed and conducted the clinical trial. M.C. and P.L.B. wrote the manuscript.

Corresponding author

Correspondence to Marta Chesi.

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Competing interests

A.K.S. served as a consultant for Novartis. S.K.K. received research support from Novartis. The LCL161 clinical trial in MM patients was funded by Novartis.

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Chesi, M., Mirza, N., Garbitt, V. et al. IAP antagonists induce anti-tumor immunity in multiple myeloma. Nat Med 22, 1411–1420 (2016). https://doi.org/10.1038/nm.4229

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