Rethinking and Retooling IL2 in the Immune Checkpoint Inhibitor Era Ryan J

VIEWS

IN THE SPOTLIGHT Back to the Future: Rethinking and Retooling IL2 in the Immune Checkpoint Inhibitor Era Ryan J. Sullivan Summary: IL2 is a type I cytokine that is associated, when given at high doses intravenously, with durable regression in a subset of patients with metastatic melanoma and renal cell carcinoma, yet high toxicity limits its use. NKTR- 214 is a novel pegylated IL2 with minor clinical activity as a single agent, but a favorable toxicity proﬁ le and compelling pharmacodynamic effects that predict utility in combination with immune checkpoint inhibition.

See related article by Bentebibel et al., p. 711 (6).

IL2, originally isolated and described as a T-cell growth control. In this issue of Cancer Discovery , Bentebibel and col- factor, is a cytokine that engages the high-affi nity IL2 recep- leagues report the phase I clinical trial results of NKTR-214 tor (IL2R) on T-effector, natural killer (NK), and T-regulatory in patients with advanced solid tumors (6 ). In all, 28 patients (Treg) cells ( 1 ). When given at high doses and intravenously were enrolled to fi ve dose levels (ranging from 0.003 mg/kg to patients with metastatic renal cell carcinoma (RCC) or to 0.012 mg/kg every 2–3 weeks). A dose-dependent increase melanoma, a subset of patients achieves complete and dura- in toxicity was seen, with the one patient treated with the ble responses that can last decades (2, 3). On the basis highest dose level (0.012 mg/kg) having developed syncope of this remarkable effi cacy, albeit for a small minority of related to hypotension. Yet in general, NKTR-214 at the other patients, high-dose IL2 (HD IL2) was approved by the FDA dose levels was well tolerated, with IL2-related symptoms like to treat metastatic RCC and melanoma in 1992 and 1998, hypotension and edema common, but typically low grade 1–2 respectively. However, the toxicity of HD IL2, which is char- and manageable with outpatient intervention. The MTD was acterized by a capillary leak syndrome that leads to car- defi ned as 0.009 mg/kg every 3 weeks and the recommended diac, pulmonary, neurologic, and renal toxicity, traditionally phase II dose was 0.006 mg/kg every 3 weeks. With regard restricted this therapy to a limited number of highly special- to effi cacy, no confi rmed responses were seen, although two ized centers and was contraindicated in patients with under- patients remained on treatment for over a year with stable lying comorbidities and/or advanced age (4 ). Furthermore, disease prior to developing disease progression. Despite a the activation of Treg cells by HD IL2, through the engage- paucity of clinical effi cacy, the correlative data from blood ment of the alpha-subunit of the IL2 receptor (CD25), was and tumor analysis of patients enrolled to this phase I trial a proposed mechanism for the rather limited therapeutic demonstrated fi ndings supporting combinatorial therapy benefi t ( 1 ). The fi nal limitation on the use of IL2 is that with NKTR-214 and immune checkpoint inhibitor therapy. immune checkpoint inhibitors, including antagonist mAbs In the peripheral blood, NKTR-214 led to increases in against CTLA4, PD-1, and PD-L1, have revolutionized the proliferation, as defi ned by the percentage of cells expressing management of RCC, melanoma, and many other malignan- the marker Ki67, of CD4+ , CD8+ , and CD56+ cells, the latter cies, and made IL2, with its high toxicity and limited effi cacy, a representative marker on NK cells. Furthermore, changes seemingly obsolete (5 ). consistent with activation of these cells were shown, includ- NKTR-214 (bempegaldesleukin) is a pegylated IL2 with, ing increases in inducible T-cell costimulator (ICOS) and on average, six releasable polyethylene glycol sites which PD-1 expression. Importantly, Treg cells hallmarked by the purportedly release in such a manner to lead to preferen- following characteristics, CD4+ , CD25hi , FOXP3+ , were mark- tial binding of the IL2R beta-gamma subunit (CD122) as edly increased in the peripheral blood on day 8 of cycles 1 and opposed to the alpha subunit, thereby promoting IL2 effects 2 and had increased evidence of proliferation (Ki67%) and on T-effector and NK cells as opposed to Treg cells. In pre- activation (ICOS%, CTLA4%). Finally, the pharmacodynamic clinical models, this led to a signifi cant expansion of these effects of NKTR-214, specifi cally on soluble CD25 levels effector elements, without increases in Treg cells, and tumor and absolute lymphocyte count, persisted for the duration of therapy, leading to metronomic increases in response to ongoing doses. Importantly, all of these fi ndings were seen Massachusetts General Hospital Cancer Center, Boston, Massachusetts. across all dose levels tested. Corresponding Author: Ryan J. Sullivan, Massachusetts General Hospital Critically, serial biopsies were performed on a signifi - Cancer Center, 55 Fruit Street, Boston, MA 02114. Phone: 617-724-4000; cant percentage of patients enrolled to this dose-escalation Fax: 617-643-7602; E-mail: [email protected] study. This allows for more nuanced understanding of the Cancer Discov 2019;9:694–5 potential benefi ts of NKTR-214 on the tumor microenviron- doi: 10.1158/2159-8290.CD-19-0412 ment that goes beyond the modest clinical effi cacy described © 2019 American Association for Cancer Research. above. In all, 14 patients were evaluable for fl ow cytometry

694 | CANCER DISCOVERY JUNE 2019 www.aacrjournals.org

Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. VIEWS analysis of tumors obtained prior to and on therapy and NCT03138889, NCT03635983, NCT03785925), and more 12 patients had serial time points available for NanoString data than has previously been presented will be necessary to analysis using the 770 gene Human PanCancer Immune understand the impact of NKTR-214 plus immune checkpoint Profiling panels. On flow cytometry, the major findings were inhibitor therapy. However, what is absolutely clear is that there that, in general, increases in CD8+ and CD56+ cells were seen again is excitement about rediscovering the “original immuno- in the tumor microenvironment, with only a modest increase therapy” that provided the modern proof of concept that the in CD4+CD25hiFOXP3+ Treg cells. Importantly, only 4 of 14 immune system, if manipulated properly, can be weaponized patients had a clear increase in Treg cells (quantified as a powerfully against cancer. What also is clear is that NKTR-214 % of CD3+ cells) and 6 of 11 evaluable patients had a clear is not the only game in town, as other approaches evaluating the increase in CD8/Treg ratio. This data, though not overly utility of unmodified IL2 or other engineered versions of IL2 are compelling, is at least suggestive that there is preferential also ongoing (NCT03861793, NCT03875079, NCT03476174, upregulation of effector cells compared with regulatory cells NCT02989714, NCT02964078). This is remarkable news for an in the immune microenvironment that might predict more agent that had been, at least in the abstract, consigned to the efficacy as a single agent than high-dose IL2. More revealing, dustbin of history. at least with respect to combinatorial approaches utilizing NKTR-214, was the gene-expression data. Not surprisingly, Disclosure of Potential Conflicts of Interest given the known effects of IL2, marked elevation of certain R.J. Sullivan is a consultant/advisory board member for Bristol- immune-related genes were seen on-treatment compared Myers Squibb, Merck, Array Biopharma, Replimmune, Amgen, Com- with baseline. However, the list of the 62 most statistically pugen, Novartis, Syndax, and Takeda. significant differentially expressed genes (shown in Supple- Published online June 3, 2019. mentary Table S4) between baseline and on-treatment reads as a “who’s who” list of relevant immunotherapy-related genes associated with benefit and/or resistance to immune REFERENCES checkpoint inhibitor therapy. Among these are genes asso- 1. Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface ciated with T-cell activation and coinhibition (ICOS, PD-1, between tolerance and immunity. Immunity 2010;33:153–65. TIGIT, CTLA4, LAG3), immune cell–mediatedcytotoxicity 2. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, (perforin 1 and granzymes B, A, and K), the PD-1 ligands et al. High-dose recombinant interleukin 2 therapy for patients with PD-L1 and PD-L2, NK cell–regulated genes, and CD8 and metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:2105–16. Th1-associated genes (CD8A, IFNγ, CXCR3, EOMES, TBX21), 3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. as well as genes associated with recently described effec- Results of treatment of 255 patients with metastatic renal cell carci- tor memory cells associated with response to anti–PD-1 noma who received high-dose recombinant interleukin-2 therapy. J therapy (TCF7, IL7R, GZMK, CD8A, LTB; ref. 7). These find- Clin Oncol 1995;13:688–96. ings support the exploration of a number of combinatorial 4. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, approaches as simple as combined NKTR-214 with anti– Ettinghausen SE, et al. Randomized comparison of high-dose and low- PD-1/PD-L1 antibodies, taking advantage of the favorable dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol 1994;12:1572–6. immune microenvironment changes that predict benefit 5. Sullivan RJ, Atkins MB, Kirkwood JM, Agarwala SS, Clark JI, Ernstoff to anti–PD-1/PDL-1 therapy, as well as combinations with MS, et al. An update on the Society for Immunotherapy of Cancer alternative checkpoint inhibitors cotargeting one or more of consensus statement on tumor immunotherapy for the treatment of the following: TIGIT, ICOS, CTLA4, and LAG3. cutaneous melanoma: version 2.0. J Immunother Cancer 2018;6:44. In summary, the phase I trial of NKTR-214 presented here by 6. Bentebibel S-E, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Bentebibel and colleagues is emblematic of a modern early-phase Kluger HM, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced trial of an immunotherapeutic. From an efficacy standpoint, this or metastatic solid tumors. Cancer Discov 2019;9:711–21. trial did not demonstrate a clear signal yet did present illustra- 7. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins tive correlative data supporting significant clinical development RW, et al. Defining T cell states associated with response to checkpoint paths forward. A number of these are ongoing (NCT02983045, immunotherapy in melanoma. Cell 2018;175:998–1013.

JUNE 2019 CANCER DISCOVERY | 695

Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Back to the Future: Rethinking and Retooling IL2 in the Immune Checkpoint Inhibitor Era

Ryan J. Sullivan

Cancer Discov 2019;9:694-695.

Updated version Access the most recent version of this article at: http://cancerdiscovery.aacrjournals.org/content/9/6/694

Cited articles This article cites 6 articles, 3 of which you can access for free at: http://cancerdiscovery.aacrjournals.org/content/9/6/694.full#ref-list-1

Citing articles This article has been cited by 1 HighWire-hosted articles. Access the articles at: http://cancerdiscovery.aacrjournals.org/content/9/6/694.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/9/6/694. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.