Phase I Study of IPH4102, Anti‐KIR3DL2 Mab, in Relapsed/Refractory Cutaneous T‐Cell Lymphomas (CTCL): Dose‐escalation Safety, Biomarker and Clinical Activity Results

Bagot, M.; Porcu, Pierluigi; Ram‐Wolff, Caroline; Khodadoust, Michael S.; Basem, W.; Battistella, Maxime; Marie‐Cardine, Anne; Vermeer, Maarten H.; Mathieu, S.; Whittaker, Sean; Duvic, Madeleine; Bensussan, Armand; Paturel, Carine; Bonnafous, Cécile; Thonnart, Nicolas; Widemann, A.; Bonin, Cecile; Sicard, Hélène; Paiva, Christine; Pilz, Korinna; Kim, Y.H.

doi:10.1002/hon.2437_31

Cited by 9 publications

(7 citation statements)

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“…Preliminary results reveal an ORR of 45%; 10 out of 22 patients with PR, 2 CR in skin, and 5 CR in blood. Six patients developed grade 3 or more severe adverse events [ 66 ].…”

Section: Inhibitory Pathwaysmentioning

confidence: 99%

Next generation of immune checkpoint therapy in cancer: new developments and challenges

et al. 2018

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Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body’s immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

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“…Preliminary results reveal an ORR of 45%; 10 out of 22 patients with PR, 2 CR in skin, and 5 CR in blood. Six patients developed grade 3 or more severe adverse events [ 66 ].…”

Section: Inhibitory Pathwaysmentioning

confidence: 99%

Next generation of immune checkpoint therapy in cancer: new developments and challenges

et al. 2018

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“…IPH4102 is currently being investigated in the first-in-human multicenter phase I study (NCT02593045) evaluating repeated administrations at escalating doses of single-agent IPH4102 in relapsed/refractory CTCL. A recent report of this ongoing study that includes 22 CTCL patients, including 19 SS patients, indicated that IPH4102 is very well tolerated in these patients (who have had extensive treatment) with no reported treatment-related death ( 81 ). The majority of adverse effects are low grade and typical for CTCL.…”

Section: Kir3dl2 In Pathologymentioning

confidence: 99%

Therapeutic Antibodies to KIR3DL2 and Other Target Antigens on Cutaneous T-Cell Lymphomas

2017

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KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide-linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs. Beside its expression on NK cells, it is also found on rare circulating T lymphocytes, mainly CD8+. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class I molecules is essential for NK development by promoting phenomena such as licensing and driving NK cell maturation. For KIR3DL2, this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition, KIR3DL2 binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal toll-like receptor 9 that promotes cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T-cell lymphomas such as Sézary syndrome, CD30+ cutaneous lymphoma, and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies (mAbs) directed against KIR3DL2 has been helpful in the diagnosis, follow-up, and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T-cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review, we discuss the various aspects of KIR3DL2 on the functions of CD4+ T cells and how targeting this receptor helps to develop innovative therapeutic strategies.

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“…[161][162][163] The anti-CD158k mAb IPH4102 has been found to be potent and safe in preclinical studies. 164 A phase 1 study (NCT02593045) demonstrated efficacy and safety in CTCL, 165 with the expansion study ongoing. In addition, a phase 2 study (NCT03902184) of IPH4102 alone or in combination with chemotherapy is recruiting patients with advanced T-NHLs.…”

Section: Cd37mentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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Phase I Study of IPH4102, Anti‐KIR3DL2 Mab, in Relapsed/Refractory Cutaneous T‐Cell Lymphomas (CTCL): Dose‐escalation Safety, Biomarker and Clinical Activity Results

Cited by 9 publications

References 0 publications

Next generation of immune checkpoint therapy in cancer: new developments and challenges

Next generation of immune checkpoint therapy in cancer: new developments and challenges

Therapeutic Antibodies to KIR3DL2 and Other Target Antigens on Cutaneous T-Cell Lymphomas

Advances in targeted therapy for malignant lymphoma

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