Journal Article
. 2015 Jan; 3(1):2.
doi: 10.1186/s40425-014-0043-z.

Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma

Weiqing Jing 1 Jill A Gershan 1 James Weber 1 Dominique Tlomak 1 Laura McOlash 1 Catherine Sabatos-Peyton 2 Bryon D Johnson 1 
Affiliations
  • PMID: 25614821
  •     65 References
  •     46 citations

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.

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Front Immunol, 2020 Dec 18; 11. PMID: 33329549    Free PMC article.
Review.
Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach.
Mankgopo M Kgatle, Tebatso M G Boshomane, +7 authors, Mike M Sathekge.
Int J Mol Sci, 2021 May 01; 22(8). PMID: 33921181    Free PMC article.
Review.
Strategies for the Construction of Mouse Models With Humanized Immune System and Evaluation of Tumor Immune Checkpoint Inhibitor Therapy.
Wenwen Guo, Caiqin Zhang, +2 authors, Changhong Shi.
Front Oncol, 2021 May 18; 11. PMID: 33996603    Free PMC article.
Review.
Understanding LAG-3 Signaling.
Luisa Chocarro, Ester Blanco, +11 authors, David Escors.
Int J Mol Sci, 2021 Jun 03; 22(10). PMID: 34067904    Free PMC article.
Review.
5-Aminolevulinic acid/sodium ferrous citrate enhanced the antitumor effects of programmed cell death-ligand 1 blockade by regulation of exhausted T cell metabolism in a melanoma model.
Xin Hu, Weitao Que, +11 authors, Xiao-Kang Li.
Cancer Sci, 2021 May 03; 112(7). PMID: 33934440    Free PMC article.
Low-dose total body irradiation facilitates antitumoral Th1 immune responses.
Dominik Sonanini, Christoph M Griessinger, +5 authors, Manfred Kneilling.
Theranostics, 2021 Aug 03; 11(16). PMID: 34335959    Free PMC article.
Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy.
Kimiharu Takamatsu, Nobuyuki Tanaka, +21 authors, Mototsugu Oya.
Nat Commun, 2021 Sep 22; 12(1). PMID: 34545095    Free PMC article.
Tumor Microenvironment of Lymphomas and Plasma Cell Neoplasms: Broad Overview and Impact on Evaluation for Immune Based Therapies.
Sudhir Perincheri.
Front Oncol, 2021 Dec 28; 11. PMID: 34956859    Free PMC article.
Review.
Longitudinal changes of blood parameters and weight in inoperable stage III NSCLC patients treated with concurrent chemoradiotherapy followed by maintenance treatment with durvalumab.
J Guggenberger, S Kenndoff, +5 authors, F Manapov.
BMC Cancer, 2022 Mar 26; 22(1). PMID: 35331196    Free PMC article.
Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups.
Lawrence P Andrews, Hiroshi Yano, Dario A A Vignali.
Nat Immunol, 2019 Oct 16; 20(11). PMID: 31611702
Review.
The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value.
Vanessa Desantis, Francesco Domenico Savino, +5 authors, Monica Montagnani.
J Clin Med, 2022 May 15; 11(9). PMID: 35566637    Free PMC article.
Review.