vivo studies with a metastatic melanoma model showed
that IL-2/NARA1 complex resulted in an efficient expansion
of tumor-specific and polyclonal CD8+ T cells. These
CD8+ T cells showed robust interferon- production and
expressed low levels of exhaustion markers PD-1, LAG-3,
and TIM-3. These effects resulted in potent anticancer immune
responses and prolonged survival in the melanoma
tumor models. The clinical development of NARA1 is in
progress.
Bempegaldesleukin (BEMPEG, NKTR-214) is comprised
of IL-2 bound to multiple releasable polyethylene
glycol (PEG) chains through on average 6 lysine residues.
The highly PEG-ylated form is an inactive prodrug when
administered PEG chains slowly release and form active
IL-2 with conjugated fewer PEG chains. The 1-PEG-IL2
and 2-PEG-IL2 are the most active form. Due to the short
half-life, the unpegylated form of IL-2 is undetectable in
vivo as it is eliminated faster than formed. The PEG
chains on BEMPEG are located at the region of IL-2 that
contacts the CD25, reducing its ability to bind and activate
the heterotrimer,35 thus preferentially activating and
expanding effector CD8+ T and NK cells over Tregs36. In
the Phase 1 EXCEL study, 28 patients with advanced solid
tumor malignancies were treated with BEMPEG at different
doses.37 The majority of patients had a diagnosis of
metastatic RCC (15/28) or melanoma (7/28). The most
common TRAEs included fatigue, flulike symptoms, pruritus,
hypotension, rash, decreased appetite, and arthralgia
and cough. The recommended phase II dose (RP2D)
was determined to be 0.006 mg/kg q3w; 9 of 26 patients
experienced maximum tumor reductions ranging from
2% to 30%. The best overall response included SD in 14
patients. In the peripheral blood analysis, CD4+ T cells,
CD8+ T cells, and NK cells population significantly increased
with the treatment. Tumor biopsies demonstrated
increased CD8+ and NK cells in the tumor. Notably, there
was an increased amount of CD8+ and PD-1+ T cells both
in peripheral blood and in the tumor. There was a transient
increase in Tregs in the peripheral blood after treatment,
however this was not observed in tumor biopsies.
Gene expression analysis from tumor biopsies revealed
an increased expression of genes associated with T-cell infiltration
and signaling (CD3G, CD3D, CD3E, CD247,
and ZAP70; P 0.05), T-cell activation and coinhibitory
molecules (ICOS, TNFRSF9, PDCD1, CTLA4, TIGIT, and
LAG3; P 0.05), and of cytotoxic effector genes (PRF1,
GZMB, GZMA, and GZMK; P 0.05). Genes encoding for
PD-L1 and PD-L2 (CD274, PDCD1LG2; P 0.05), SOCS1,
and IDO1 were also significantly increased. Several other
studies evaluated the combination of checkpoint inhibitors
and NKTR-214 listed in Table 1. The Phase 1/2
PIVOT-02 trial has evaluated the safety and efficacy of BEMPEG
in combination with nivolumab in advanced solid
tumors. Based on the dose-escalation phase patients received
0.006mg/kg and 360mg nivolumab IV every 3
weeks. The expansion cohort includes 5 different tumor
types, including RCC, melanoma, NSCLC, urothelial and
triple-negative breast cancer. Preliminary analysis of 34
metastatic urothelial cancer patients treated in this trial
showed ORR was 48% (11/23; 95% CI 27–69%) with a
17% CR rate (4/23) and 70% (16/23) DCR. 6/10 (60%) PDL1
negative tumor at baseline converted to PD-L1+ at
week 3.38 With these promising results, the PIVOT-09,
the Phase 3 study of BEMPEG in combination with NIVO
compared with the investigator’s choice of a TKI therapy
(either sunitinib or cabozantinib monotherapy) for advanced
mRCC, started recruiting in December 2018.
Conclusion
IL-2 is an excellent example of how a deep understanding
of biology can help us to re-utilize “old” compounds on
the shelf with enhanced capacities. Notably, the novel
modified IL-2 and IO combination treatments showed
the promise to overcome immune checkpoint monotherapy
resistance. Additionally, they have a significantly better
toxicity profile than the high dose IL-2 with availa-
bility to use in the outpatient setting. However, to date,
we do not know which of the above mentioned approaches
of combination treatments will be the best in
RCC patients with the least toxicity and the best efficacy.
Future biomarker based clinical and preclinical studies
will help to elucidate these questions.
References
1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015; 373:
1803-1813.
2. Motzer RJ, Tannir NM, McDermott DF et al. Nivolumab plus Ipilimumab
versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J
Med. 2018; 378: 1277-1290.
3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus
Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380:
1116-1127.
4. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus
Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380:
1103-1115.
5. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes
from normal human bone marrows. Science 1976; 193: 1007-
1008.
6. Mier JW, Gallo RC. Purification and some characteristics of human
T-cell growth factor from phytohemagglutinin-stimulated lymphocyteconditioned
media. Proc Natl Acad Sci U S A 1980; 77: 6134-6138.
7. Revised nomenclature for antigen-nonspecific T cell proliferation and
helper factors. J Immunol. 1979; 123: 2928-2929.
8. Devos R, Plaetinck G, Cheroutre H et al. Molecular cloning of human
interleukin 2 cDNA and its expression in E. coli. Nucleic Acids Res. 1983;
11: 4307-4323.
9. Taniguchi T, Matsui H, Fujita T et al. Structure and expression of a
cloned cDNA for human interleukin-2. Nature. 1983; 302: 305-310.
10. Bazan JF. Unraveling the structure of IL-2. Science 1992; 257: 410-
413.
11. Wagner H, Hardt C, Heeg K et al. T-cell-derived helper factor allows
in vivo induction of cytotoxic T cells in nu/nu mice. Nature. 1980; 284:
278-278.
12. Reimann J, Diamantstein T. Interleukin-2 allows in vivo induction
of anti-erythrocyte autoantibody production in nude mice associated
with the injection of rat erythrocytes. Clin Exp Immunol. 1981; 43: 641-
644.
13. Cheever MA, Greenberg PD, Fefer A, Gillis S. Augmentation of the
anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by
in vivo administration of purified interleukin 2. J Exp Med. 1982; 155:
968-980.
14. Lafreniere R, Rosenberg SA. Successful immunotherapy of murine
experimental hepatic metastases with lymphokine-activated killer cells
and recombinant interleukin 2. Cancer Res. 1985; 45: 3735-3741.
15. Lotze MT, Chang AE, Seipp CA, et al. High-dose recombinant interleukin
2 in the treatment of patients with disseminated cancer. Responses,
treatment-related morbidity, and histologic findings. JAMA.
1986; 256: 3117-3124.
16. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive
patients with metastatic melanoma or renal cell cancer using highdose
bolus interleukin 2. JAMA. 1994; 271: 907-913.
17. Rosenberg SA. IL-2: the first effective immunotherapy for human
cancer. J Immunol. 2014; 192: 5451-5458.
18. Jain J, Loh C, Rao A. Transcriptional regulation of the IL-2 gene. Curr
Opin Immunol. 1995; 7: 333-342.
Kidney Cancer Journal 23