ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients

Trédan, Olivier; Ménétrier‐Caux, Christine; Ray‐Coquard, Isabelle; Garin, Gwenaëlle; Cropet, Claire; Verronèse, Estelle; Bachelot, Thomas; Rebattu, P.; Heudel, Pierre; Cassier, Philippe; Chabaud, Sylvie; Croughs, Thérèse; Dupont, Patricia; Cadore, Anne-claire; Clapisson, Gilles; Delgado, Ana Sofia; Bardin-Dit-Courageot, Christine; Rigal, Chantal; N'Kodia, Axelle; Gilles-Afchain, L.; Morre, Michel; Pérol, David; Blay, Jean‐Yves; Caux, Christophe

doi:10.1093/annonc/mdx058

Cited by 40 publications

(20 citation statements)

References 38 publications

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“…Owing to the capacity of T-cell expansion without severe toxicity, exogenous administration of IL-7 has been considered a beneficial therapy for cancer patients; [35][36][37][38][39] however, antitumor responses and regulation of TME mediated by IL-7 treatment remain unknown. This study shows that systemic administration of rhIL-7-hyFc, a longacting form of recombinant human IL-7, elicits antitumor effect through induction and maintenance of an inflamed and immunostimulatory TME (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

Kim

Choi³

et al. 2020

Clin & Trans Imm

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Objectives Emerging oncotherapeutic strategies require the induction of an immunostimulatory tumor microenvironment (TME) containing numerous tumor‐reactive CD8+ T cells. Interleukin‐7 (IL‐7), a T‐cell homeostatic cytokine, induces an antitumor response; however, the detailed mechanisms underlying the contributions of the IL‐7 to TME remain unclear. Here, we aimed to investigate the mechanism underlying the induction of antitumor response by hybrid Fc‐fused long‐acting recombinant human IL‐7 (rhIL‐7‐hyFc) through regulation of both adaptive and innate immune cells in the TME. Methods We evaluated rhIL‐7‐hyFc‐mediated antitumor responses in murine syngeneic tumor models. We analysed the cellular and molecular features of tumor‐infiltrating lymphocytes (TILs) and changes in the TME after rhIL‐7‐hyFc treatment. Furthermore, we evaluated the antitumor efficacy of rhIL‐7‐hyFc combined with chemotherapy and checkpoint inhibitors (CPIs). Results Systemic delivery of rhIL‐7‐hyFc induced significant therapeutic benefits by expanding CD8+ T cells with enhanced tumor tropism. In tumors, rhIL‐7‐hyFc increased both tumor‐reactive and bystander CD8+ TILs, all of which displayed enhanced effector functions but less exhausted phenotypes. Moreover, rhIL‐7‐hyFc suppressed the generation of immunosuppressive myeloid cells in the bone marrow of tumor‐bearing mice, resulting in the immunostimulatory TME. Combination therapy with chemotherapy and CPIs, rhIL‐7‐hyFc elicited a strong antitumor response and even under a T lymphopenic condition by restoring CD8+ T cells. When combined with chemotherapy and CPIs, rhIL‐7‐hyFc administration enhanced antitumor response under intact andlymphopenic conditions by restoring CD8+ T cells. Conclusion Taken together, these data demonstrate that rhIL‐7‐hyFc induces antitumor responses by generating T‐cell‐inflamed TME and provide a preclinical proof of concept of immunotherapy with rhIL‐7‐hyFc to enhance therapeutic responses in the clinic.

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Section: Discussionmentioning

confidence: 99%

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

Kim

Choi³

et al. 2020

Clin & Trans Imm

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“…Decreased Treg frequency was an important distinction from treatments with IL-2, a related γc cytokine, which had the opposite effect. A study in lymphopenic breast cancer patients showed that IL-7 treatment before (but not during) chemotherapy increased CD4 counts 115 . A trial in pediatric sarcoma patients combined a tumor vaccine with IL-7, confirming IL-7 induced an increase in T-cells and and decreased Treg frequency, but without anti-cancer benefit 116 .…”

Section: Il-7 Traction For Therapeutic Purposes Il-7 Administration Imentioning

confidence: 99%

Flip the coin: IL-7 and IL-7R in health and disease

2019

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Interleukin (IL)-7 and its receptor (IL-7R) are critical for T-and, in the mouse, B-cell development, as well as differentiation and survival of naïve T-cells, and generation and maintenance of memory T-cells. They are also required for innate lymphoid cell development and maintenance, and consequently for the generation of lymphoid structures and barrier defense. Here, we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impacts of its deregulation, placing a particular emphasis on its 'dark side' as a promoter of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7/IL-7R signaling axis.

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“…Importantly, rhIL-7 therapy also increased the numbers of CD4 + recent thymic emigrants (RTEs), the signal joint to β TREC ratio and TCR repertoire diversity in some participants, effects that imply enhanced thymic activity (Box 2). Subsequently, two other clinical trials (NCT01190111 and NCT01241643) demons trated that repeated doses of rhIL-7 were well tolerated and resulted in sustained CD4 + T cell numbers in the majority of HIV-infected participants [140][141][142][143] . Similarly, in a phase I/IIa dose-escalation trial (NCT00839436) in patients with idiopathic CD4 + lymphopenia at risk of disease progression, rhIL-7 led to an increase in the number of circulating CD4 + and CD8 + T cells and tissue-resident CD3 + T cells in the gut mucosa and BM.…”

Section: Cytokine Receptor Common Subunit-γmentioning

confidence: 99%

T cell regeneration after immunological injury

2020

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Recovery of immunocompetence after periods of haematopoietic stress or injury is crucial not only for efficient responses against pathogens and tumour antigens but also for optimal responses to immunotherapy for cancer. In contrast to the early recovery of innate cells, including neutrophils, natural killer (NK) cells and monocytes, adaptive immune cells, in particular T cells, recover at a much slower pace and are particularly sensitive to negative insults caused by infections or cytoreductive chemotherapy and radiotherapy. Constrictions in the diversity of the T cell pool have been associated with impaired immune responses to several antigens 1-3 and adverse clinical outcomes in patients receiving haematopoietic cell transplantation (HCT) 4,5. The capacity of T cells to mount and maintain effective responses to a wide variety of antigens depends on a large repertoire of unique T cell receptors (TCRs) generated in the thymus during the process of T cell development. This process is dependent on crosstalk between bone marrow (BM)-derived T cell progenitors and the supportive thymic stromal microenvironment, which primarily consists of thymic epithelial cells (TECs), endothelial cells, mesenchymal stromal cells, dendritic cells and macrophages 6. Although, for example, T cell proliferation, driven by interleukin-7 (IL-7) and IL-15, in response to lymphopenic conditions can contribute to numerical reconstitution of T cells, complete long-term recovery of a diverse and functional T cell pool requires reactivation of thymic function and de novo T cell generation (Fig. 1). However, the thymus is sensitive to various injuries, such as those caused by cytoreductive treatments, infection, septic shock and graft-versus-host disease (GVHD). Furthermore,

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ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients

Cited by 40 publications

References 38 publications

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

Flip the coin: IL-7 and IL-7R in health and disease

T cell regeneration after immunological injury

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