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

Korde, Neha; Carlsten, Mattias; Lee, Min Jung; Minter, Alex; Tan, Esther; Kwok, Mary; Manasanch, Elisabet E.; Bhutani, Manisha; Tageja, Nishant; Roschewski, Mark; Zingone, Adriana; Costello, Rene; Mulquin, Marcia; Zuchlinski, Diamond; Marić, Irina; Calvo, Katherine R.; Braylan, Raul C.; Tembhare, Prashant; Yuan, Constance; Stetler‐Stevenson, Maryalice; Trepel, Jane B.; Childs, Richard W.; Landgren, Ola

doi:10.3324/haematol.2013.103085

Cited by 113 publications

(82 citation statements)

References 14 publications

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“…Although no objective responses were seen, IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation [66]. The following Phase II clinical trial was recently completed in SMM patients where immune cells are still intact [65]. Encouragingly, results from this trial showed that NK cells elicit a tumor specific cytotoxic response, without harming normal cells [65].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…The following Phase II clinical trial was recently completed in SMM patients where immune cells are still intact [65]. Encouragingly, results from this trial showed that NK cells elicit a tumor specific cytotoxic response, without harming normal cells [65]. This early clinical activity suggests that a more efficacious treatment strategy of manipulating the immune system with blockers of inhibitory NK cell function might improve anti-MM responses induced by anti-BCMA mAbs.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…On the other hand, BiTEs, as opposed to CAR T cells, may not stimulate persistent immunity against tumor cells, since CAR T cells can expand in vivo, with memory CAR T cells detected following months of administration. Besides the manipulation of T cells, blocking the function of inhibitory killer cell immunoglobulin-like receptors (KIRs) [65][66][67][68] or CD200R [69][70][71][72] may enhance NK cell function, thereby leading to enhanced ADCC to lyse MM cells by anti-BCMA mAbs. Specifically, the anti-KIR (KIR2DL1/L2/L3 and KIR2DS1/S2) antagonist antibody IPH2101, combined with lenalidomide was completed in a Phase I trial of patients with MM experiencing a first or second relapse [66].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Targeting B-Cell Maturation Antigen in Multiple Myeloma

2015

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Novel effective immunotherapies are needed for patients with multiple myeloma (MM), since disease recurrence remains a major obstacle. B-cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells , has emerged as a very selective antigen to be targeted in novel treatments for MM. We here first review BCMA-related biology, and then highlight the recent clinical development of a novel afucosylated anti-BCMA monoclonal antibody conjugated with monomethyl auristatin F via noncleavable linker (GSK2857916). Chimeric antigen receptor-expressing T cells targeting BCMA may also induce specific and durable anti-MM responses by patients’ own effector cells. Clinical trials testing these two approaches (NCT02064387, NCT02215967) are currently ongoing in relapsed and refractory MM patients.

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Section: Conclusion and Future Perspectivementioning

confidence: 99%

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Section: Conclusion and Future Perspectivementioning

confidence: 99%

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Targeting B-Cell Maturation Antigen in Multiple Myeloma

2015

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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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“…Novel tumor immunotherapies have been developed that block the inhibitory killer immunoglobinlike receptors (KIRs) on human NK cells that are functionally homologous to murine Ly49s (4). However, clinical trials of anti-KIR checkpoint blockade failed to show efficacy in treating patients with smoldering multiple myeloma (5). A better understanding of the in vivo functions of inhibitory NK-cell receptors is important for improving checkpoint blockade of NK cells.…”

mentioning

confidence: 99%

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Bern

Beckman

Ebihara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

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

Abstract: LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o n

Cited by 113 publications

References 14 publications

Targeting B-Cell Maturation Antigen in Multiple Myeloma

Targeting B-Cell Maturation Antigen in Multiple Myeloma

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

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