A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma

Benson, Don M.; Hofmeister, Craig C.; Padmanabhan, Swaminathan; Suvannasankha, Attaya; Jagannath, Sundar; Abonour, Rafat; Bakan, Courtney E.; Pèlegrin, André; Efebera, Yvonne A.; Tiollier, Jérôme; Caligiuri, Michael A.; Farag, Sherif

doi:10.1182/blood-2012-06-438028

Cited by 213 publications

(185 citation statements)

References 31 publications

(47 reference statements)

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“…We, therefore, measured the proportion of free ligand-bindable KIR2D receptors throughout the trial using previously described methods. 10,11 Ligand-bindable KIR2D expression was found to decrease to 0% in all 9 subjects 24 h after first infusion ( Figure 1B). In 6 out of 8 patients, this level was maintained at less than 50% compared to baseline when measured prior to each subsequent IPH2101 infusion, suggesting that IPH2101 treatment was able to significantly reduce ligand-bindable KIR2D levels for up to 60 days following each infusion in most patients.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

et al. 2014

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

et al. 2014

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“…This approach, analogous to checkpoint blockade in T cells (6), resulted in increased rejection of MHC class I-expressing malignant cells caused by a liberated NK cell response to leukemia cells (7)(8)(9). This strategy has now been tested as anti-KIR therapy in clinical trials: a phase I trial for acute myeloid leukemia (AML) and a phase II trial for myeloma (10)(11)(12). The second immunotherapy setting is adoptive transfer of mature NK cells across a "missing self-barrier," i.e., to cancer patients lacking MHC class I molecules of the donor (13,14).…”

Section: Introductionmentioning

confidence: 99%

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Wagner

Wickström

Tallerico

et al. 2016

Cancer Immunology Research

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Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graftversus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials. Both approaches are challenged by the emerging concept that NK cells may constantly adapt or "tune" their responsiveness according to the amount of self MHC class I that they sense on surrounding cells. Hence, these therapeutic attempts would initially result in increased killing of tumor cells, but a parallel adaptation process might ultimately lead to impaired antitumor efficacy. We have investigated this question in two mouse models: inhibitory receptor blockade in vivo and adoptive transfer to MHC class I-disparate hosts. We show that changed self-perception via inhibitory receptors in mature NK cells reprograms the reactivity such that tolerance to healthy cells is always preserved. However, reactivity against cancer cells lacking critical MHC class I molecules (missing self-reactivity) still remains or may even be increased. This dissociation between activity against healthy cells and tumor cells may provide an answer as to why NK cells mediate graftversus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy.

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“…In fact, treatment of mice bearing the lenalidomide-resistant RMA T-cell lymphoma with this combination led to in vivo tumor elimination [102]. Recently, the results of a phase I and a phase II clinical trial with IPH2101 have been reported in patients with relapsed/refractory or smoldering MM, respectively [103,104]. Although deemed safe, the phase II clinical trial showed no clinical response to IPH2101 alone.…”

Section: Adoptive Nk-cell Transfermentioning

confidence: 99%

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Binsfeld

Fostier

Muller

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models.

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A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma

Abstract: Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM);

Cited by 213 publications

References 31 publications

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

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