J Immunother Cancer. 2015 Jan 20;3(1):2. doi: 10.1186/s40425-014-0043-z. eCollection 2015.
Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma.
Journal for immunotherapy of cancer
Weiqing Jing, Jill A Gershan, James Weber, Dominique Tlomak, Laura McOlash, Catherine Sabatos-Peyton, Bryon D Johnson
Affiliations
Affiliations
- Division of Hematology/Oncology/Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226 USA.
- Novartis Institutes for BioMedical Research, Inc., Cambridge, MA 02139 USA.
PMID: 25614821
PMCID: PMC4302511 DOI: 10.1186/s40425-014-0043-z
Abstract
BACKGROUND: Multiple myeloma is characterized by the presence of transformed neoplastic plasma cells in the bone marrow and is generally considered to be an incurable disease. Successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments. Our lab previously showed that a combination of transient lymphodepletion (sublethal whole body irradiation) and PD-1/PD-L1 blockade generated anti-myeloma T cell reactivity capable of eliminating established disease. We hypothesized that blocking a combination of checkpoint receptors in the context of low-dose, lymphodepleting whole body radiation would boost anti-tumor immunity.
METHODS: To test our central hypothesis, we utilized a 5T33 murine multiple myeloma model. Myeloma-bearing mice were treated with a low dose of whole body irradiation and combinations of blocking antibodies to PD-L1, LAG-3, TIM-3, CD48 (the ligand for 2B4) and CTLA4.
RESULTS: Temporal phenotypic analysis of bone marrow from myeloma-bearing mice demonstrated that elevated percentages of PD-1, 2B4, LAG-3 and TIM-3 proteins were expressed on T cells. When PD-L1 blockade was combined with blocking antibodies to LAG-3, TIM-3 or CTLA4, synergistic or additive increases in survival were observed (survival rates improved from ~30% to >80%). The increased survival rates correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells. When stimulated in vitro with myeloma cells, CD8 T cells from treated mice produced elevated levels proinflammatory cytokines. Cytokines were spontaneously released from CD4 T cells isolated from mice treated with PD-L1 plus CTLA4 blocking antibodies.
CONCLUSIONS: These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation. This strategy is a promising combination strategy for myeloma and other hematologic malignancies.
Keywords: 2B4; Blockade; CTLA4; Immune checkpoint proteins; LAG-3; Low dose whole body irradiation; Myeloma; PD-L1; TIM-3
References
- Trends Immunol. 2012 Jul;33(7):364-72 - PubMed
- N Engl J Med. 2013 Jul 11;369(2):122-33 - PubMed
- Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4275-80 - PubMed
- Trends Mol Med. 2008 Dec;14(12):550-9 - PubMed
- Exp Hematol. 2010 Feb;38(2):124-31 - PubMed
- Eur J Immunol. 2012 Mar;42(3):651-61 - PubMed
- Cancer Immunol Res. 2014 May;2(5):410-22 - PubMed
- Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7875-80 - PubMed
- Clin Cancer Res. 2010 Dec 15;16(24):6019-28 - PubMed
- Biochim Biophys Acta. 2013 Aug;1836(1):177-85 - PubMed
- J Immunol. 2011 Apr 1;186(7):4200-12 - PubMed
- J Clin Oncol. 2010 Jul 1;28(19):3167-75 - PubMed
- Cancer Res. 2014 Feb 15;74(4):1045-55 - PubMed
- Cancer Res. 2013 Jan 15;73(2):605-16 - PubMed
- Science. 1995 Nov 10;270(5238):985-8 - PubMed
- N Engl J Med. 2012 Jun 28;366(26):2443-54 - PubMed
- Clin Cancer Res. 2009 Feb 1;15(3):971-9 - PubMed
- Biol Blood Marrow Transplant. 2011 Aug;17 (8):1133-45 - PubMed
- J Immunother. 2010 Apr;33(3):225-35 - PubMed
- Cancer Res. 2014 Jul 1;74(13):3418-28 - PubMed
- Clin Cancer Res. 2013 Jan 15;19(2):462-8 - PubMed
- Nat Immunol. 2011 Jun;12(6):492-9 - PubMed
- J Immunol. 1998 Apr 15;160(8):3855-60 - PubMed
- Cancer Immunol Res. 2014 Feb;2(2):142-53 - PubMed
- Clin Cancer Res. 2013 Oct 15;19(20):5626-35 - PubMed
- Nat Rev Immunol. 2008 Jun;8(6):467-77 - PubMed
- Front Immunol. 2013 Dec 19;4:455 - PubMed
- PLoS One. 2014 May 05;9(5):e93523 - PubMed
- Immunity. 2014 Feb 20;40(2):289-302 - PubMed
- Cancer Res. 2011 May 15;71(10 ):3540-51 - PubMed
- Cell Immunol. 2012 Jul-Aug;278(1-2):76-83 - PubMed
- Blood. 2010 Sep 30;116(13):2286-94 - PubMed
- J Exp Med. 2000 Jul 17;192(2):303-10 - PubMed
- Clin Cancer Res. 2007 Apr 1;13(7):2151-7 - PubMed
- J Exp Med. 2010 Sep 27;207 (10 ):2187-94 - PubMed
- Cancer Immunol Res. 2014 May;2(5):393-8 - PubMed
- J Immunol. 2012 Apr 1;188(7):2957-65 - PubMed
- N Engl J Med. 2010 Aug 19;363(8):711-23 - PubMed
- J Immunother. 2011 Jun;34(5):409-18 - PubMed
- J Clin Invest. 2012 Apr;122(4):1271-82 - PubMed
- J Exp Med. 2009 Aug 3;206(8):1717-25 - PubMed
- J Clin Invest. 2011 Jun;121(6):2350-60 - PubMed
- PLoS Pathog. 2011 May;7(5):e1002045 - PubMed
- Annu Rev Immunol. 2005;23:515-48 - PubMed
- Science. 2007 Nov 16;318(5853):1141-3 - PubMed
- Immunity. 2007 Oct;27(4):670-84 - PubMed
- Cancer Res. 2012 Oct 15;72(20):5209-18 - PubMed
- J Clin Invest. 2014 May;124(5):2246-59 - PubMed
- J Immunol. 2011 Oct 1;187(7):3493-8 - PubMed
- Oncoimmunology. 2012 Nov 1;1(8):1239-1247 - PubMed
- Semin Oncol. 2010 Oct;37(5):499-507 - PubMed
- Cancer Res. 2014 Jan 15;74(2):633-4; discussion 635 - PubMed
- Cancer Res. 2012 Feb 15;72(4):917-27 - PubMed
- J Exp Med. 2010 Sep 27;207 (10 ):2175-86 - PubMed
- J Immunol. 2013 May 1;190(9):4899-909 - PubMed
- Immunology. 2010 Apr;129(4):474-81 - PubMed
- Cancer Immunol Immunother. 2013 Apr;62(4):629-37 - PubMed
- Int Immunol. 2005 Feb;17(2):133-44 - PubMed
- J Immunol. 2001 Dec 15;167(12 ):6706-10 - PubMed
- Blood. 2007 Jul 1;110(1):296-304 - PubMed
- J Immunol. 2006 Mar 1;176(5):2758-64 - PubMed
- Blood. 2011 Apr 28;117(17 ):4501-10 - PubMed
- J Exp Med. 2013 Aug 26;210(9):1695-710 - PubMed
- Br J Haematol. 2012 Jan;156(2):213-24 - PubMed
- J Immunol. 2013 Jun 1;190(11):5620-8 - PubMed
Publication Types