T cell‐based targeted immunotherapies for patients with multiple myeloma

Wang, Lei; Jin, Nan; Schmitt, Anita; Greiner, Jochen; Malcherek, Georg; Hundemer, Michael; Mani, Jiju; Hose, Dirk; Raab, Marc-Steffen; Ho, Anthony D.; Chen, Bao An; Goldschmidt, Hartmut; Schmitt, Michael

doi:10.1002/ijc.29190

Cited by 11 publications

(9 citation statements)

References 205 publications

(203 reference statements)

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“…We identified 73 different HLA ligands representing 22 of 25 (88%) previously described myeloma antigens. 42 We found 9 of the 22 detectable antigens (41%) to be exclusively presented on MM samples, 10 of 22 antigens (45.5%) to be represented both on MM and HV samples, and 3 of 22 (13.6%) exclusively presented on HV-derived samples ( Figure 3A). Of note, 7 of 9 MMexclusive antigens (77.8%) were only detectable on MCLs.…”

Section: Blood 3 September 2015 X Volume 126 Number 10 T-cell Epitomentioning

confidence: 76%

“…[25][26][27][28][29][30][31][32][33][34][35] However, these studies were limited in scope of antigens and HLA allotypes. 42 In our previous studies in acute myeloid leukemia and chronic lymphocytic leukemia, we demonstrated that the comprehensive and comparative analysis of the HLA-presented antigenome can identify extensive panels of broadly presented T-cell epitopes covering a multitude of HLA allotypes. 12,13 Here, we translated this systematic approach to MM.…”

Section: Discussionmentioning

confidence: 93%

“…However, broad clinical effectiveness has not yet been achieved. These previous studies were restricted to very few HLA allotypes and single antigens/epitopes, 42 limiting both the population of patients eligible for this therapeutic approach and the spectrum of inducible tumor-specific T-cell responses. Of note, recent studies demonstrated lacking degrees of tumor association for several of these tumor antigens, both on the transcriptome level 43 and importantly also on the level of HLA-restricted presentation.…”

Section: Introductionmentioning

confidence: 99%

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The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

Walz

Stickel

Kowalewski

et al. 2015

Blood

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Key Points• Direct analysis of the HLApresented peptidome identifies a distinct antigenic signature in MM.• T-cell responses for these antigens are detectable exclusively in MM patients and can be induced in vitro in response-naive patients.Direct analysis of HLA-presented antigens by mass spectrometry provides a comprehensive view on the antigenic landscape of different tissues/malignancies and enables the identification of novel, pathophysiologically relevant T-cell epitopes. Here, we present a systematic and comparative study of the HLA class I and II presented, nonmutant antigenome of multiple myeloma (MM). Quantification of HLA surface expression revealed elevated HLA molecule counts on malignant plasma cells compared with normal B cells, excluding relevant HLA downregulation in MM. Analyzing the presentation of established myeloma-associated T-cell antigens on the HLA ligandome level, we found a substantial proportion of antigens to be only infrequently presented on primary myelomas or to display suboptimal degrees of myeloma specificity. However, unsupervised analysis of our extensive HLA ligand data set delineated a panel of 58 highly specific myeloma-associated antigens (including multiple myeloma SET domain containing protein) which are characterized by frequent and exclusive presentation on myeloma samples. Functional characterization of these target antigens revealed peptide-specific, preexisting CD8 1 T-cell responses exclusively in myeloma patients, which is indicative of pathophysiological relevance.Furthermore, in vitro priming experiments revealed that peptide-specific T-cell responses can be induced in response-naive myeloma patients. Together, our results serve to guide antigen selection for T-cell-based immunotherapy of MM. (Blood. 2015;126(10):1203-1213

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Section: Blood 3 September 2015 X Volume 126 Number 10 T-cell Epitomentioning

confidence: 76%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

Walz

Stickel

Kowalewski

et al. 2015

Blood

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“…Therapeutic monoclonal antibodies (mAbs) such as IPH2101 comprise just one dimension (28) of the promising, rapidly expanding field of immunotherapy for MM which also includes NK- and T-cellular therapies (29,30), vaccines (30) and immunomodulating agents, among others. Tumor-directed mAbs (31,32) as well as effector cell-targeted mAbs (21,22,33) provide an opportunity for increasing precision with which to modulate immunity against MM, as well.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma

Benson

Cohen

Jagannath

et al. 2015

Clinical Cancer Research

159

125

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PURPOSE Natural killer (NK) cells may play an important role in the immune response to multiple myeloma (MM); however, MM cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against MM; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class anti-inhibitory KIR antibody, has acceptable safety and tolerability in MM as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for MM. EXPERIMENTAL DESIGN A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10mg on cohort 1 and 25mg on cohorts 2 and 3 days 1–21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg on cohort 1, 1mg/kg on cohort 2, and 2mg/kg on cohort 3. No corticosteroids were utilized. The primary endpoint was safety, secondary endpoints included clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD). RESULTS The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single agent IPH2101 trial. Five serious adverse events (SAEs) were reported. Five objective responses occurred. No autoimmunity was seen. CONCLUSIONS These findings suggest that lenalidomide in combination with anti-inhibitory KIR therapy warrants further investigation in MM as a steroid-sparing, dual immune therapy. This trial was registered at www.clinicaltrials.gov (reference: NCT01217203).

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“…For example, although sclerostin null mice have high bone mineral density, they have increased B-cell apoptosis due to decreased osteoblast-derived CXCL12, resulting from increased Wnt signaling [71]. Moreover, although the immune system in general suppresses multiple myeloma [72], not all immune cells mediate this role. Regulatory T-cells and immunosuppressive myeloid-derived suppressor cells [73] are now being identified as important new targets that inhibit the immune response in multiple myeloma [74].…”

Section: Effects Of Osteoblasts On Multiple Myelomamentioning

confidence: 99%

Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

Reagan

Liaw

Rosen

et al. 2015

Bone

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Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast.

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T cell‐based targeted immunotherapies for patients with multiple myeloma

Cited by 11 publications

References 205 publications

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma

Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

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