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Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

ABSTRACT: High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2R?). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-? and TNF-?. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.

SUBMITTER: Sharma M

PROVIDER: S-EPMC6994577 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

Sharma Meenu M Khong Hiep H Fa'ak Faisal F Bentebibel Salah-Eddine SE Janssen Louise M E LME Chesson Brent C BC Creasy Caitlin A CA Forget Marie-Andrée MA Kahn Laura Maria S LMS Pazdrak Barbara B Karki Binisha B Hailemichael Yared Y Singh Manisha M Vianden Christina C Vennam Srinivas S Bharadwaj Uddalak U Tweardy David J DJ Haymaker Cara C Bernatchez Chantale C Huang Shixia S Rajapakshe Kimal K Coarfa Cristian C Hurwitz Michael E ME Sznol Mario M Hwu Patrick P Hoch Ute U Addepalli Murali M Charych Deborah H DH Zalevsky Jonathan J Diab Adi A Overwijk Willem W WW

Nature communications 20200131 1

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 ...[more]

PMID: 32005826

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Project description:Tumor-reactive CD8 T cells found in cancer patients are frequently dysfunctional, unable to halt tumor growth. Adoptive T cell transfer (ACT), the administration of large numbers of in vitro-generated cytolytic tumor-reactive CD8 T cells, is an important cancer immune therapy being pursued. However, a limitation of ACT is that transferred CD8 T cells often rapidly lose effector function, and despite exciting results in certain malignancies, few ACT clinical trials have shown responses in solid tumors. Here, we developed preclinical cancer mouse models to investigate if and how tumor-specific CD4 T cells can be enlisted to overcome CD8 T cell dysfunction in the setting of ACT. In situ confocal microscopy of color-coded cancer cells, tumor-specific CD8 and CD4 T cells, and antigen presenting cells (APC), combined with functional studies, revealed that the spatial positioning and interactions of CD8 and CD4 T cells, but not their numbers, dictates ACT efficacy and anti-tumor responses. We uncover a new role of antigen-specific CD4 T cells in addition to the known requirement for CD4 T cells during priming/activation of naïve CD8 T cells. CD4 T cells must co-engage with CD8 T cells and APC cross-presenting CD8- and CD4-tumor antigens during the effector phase, forming a three-cell-cluster (triad), to license CD8 T cell cytotoxicity and mediate cancer cell elimination. Triad formation transcriptionally and epigenetically reprogram CD8 T cells, prevent T cell dysfunction/exhaustion, and ultimately lead to the elimination of large established tumors and confer long-term protection from recurrence. When intratumoral triad formation was disrupted, adoptively transferred CD8 T cells could not be reprogrammed, and tumors progressed despite equal numbers of tumor-infiltrating CD8 and CD4 T cells. Strikingly, the formation of CD4 T cell::CD8 T cell::APC triads in tumors of patients with lung cancers treated with immune checkpoint blockade was associated with clinical responses, but not CD4::APC dyads or overall numbers of CD8 or CD4 T cells, demonstrating the importance of triads in non-ACT settings in humans. Our work uncovers intratumoral triads as a key requirement for anti-tumor immunity and a new role for CD4 T cells in CD8 T cell cytotoxicity and cancer cell eradication.

Dataset Information

Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

Publications

Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

Similar Datasets

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