Kidney Cancer Journal 19
Back to Interleukin 2 After Four Decades:
Review of the History, Biology, Novel Approaches
and Clinical Trials
Elshad Hasanov,
MD PhD1
Adi Diab, MD2 Nizar M. Tannir,
MD, FACP1
1 Department of Genitourinary Medical Oncology, Division of Cancer Medicine,
MD Anderson Cancer Center, Houston, TX
2 Department of Melanoma Medical Oncology, Division of Cancer Medicine,
MD Anderson Cancer Center, Houston, TX
Introduction
After the discovery of checkpoint inhibitors (IO), the
treatment landscape of renal cell carcinoma (RCC) rapidly
transformed from VEGF based treatments to IO and
IO+TKI combinations. Within the last 5 years, the Food
and Drug Administration (FDA) approved several IO and
combination regimens for the treatment of renal cell carcinoma.
In 2015, nivolumab was approved for second
line treatment based on the Checkmate 025 study.1 Then
in 2018, nivolumab+ipilimumab, followed by pembrolizumab+
axitinib and avelumab+axitinib in 2019, was
approved for the first line treatment of RCC based on
Checkmate 214, Keynote 426 and Javelin Renal 101 studies,
respectively.2-4 These trials demonstrated improved
efficacy of novel combinations compared to sunitinib in
some patients; however, achieving durable response remained
a challenge. Along with many other strategies addressing
each mechanism, one of the approaches was to
revisit IL-2 based treatments and evaluate the combinations
with IO. This review will describe the historical discovery,
development of Interleukin-2 (IL-2) immuno-
therapy, related biology and limitation in early studies.
Additionally, we will review the novel approaches to
modify IL-2 and summarize related clinical studies.
Discovery of IL-2 and Early Clinical Trials
The beginning of the IL-2 story started 45 years ago, in
1975, with the discovery of Dr Gallo and his team (Figure
1). For the first time, they showed that there is a selective
growth of T lymphocytes when unfractionated normal
bone marrow cells were cultured with the conditioned
medium, which was obtained from phytohemagglutininstimulated
normal human lymphocytes.5 Later, his group
purified the so-called “human T-cell growth factor”
(TCGF) from the phytohemagglutinin (PHA)-stimulated
lymphocyte-conditioned media.6 Several other laboratories
described many properties of this cytokine, using different
names: Thymocyte Mitogenic Factor (TMF),
Co-stimulator, Killer cell helper factor (KHF), Secondary
cytotoxic T cell-inducing factor (SCIF). During the Second
International Lymphokine Workshop, Switzerland in
1979, to decrease the redundancy and confusion, the interleukin
nomenclature was revised, previously called
TCGF, TMF, SCIF, KHF and then renamed as Interleukin-
2.7 It was described as a cytokine that induces primary cytotoxic
T cell responses and promotes and maintains the
viability and proliferation of primary T cell lines in invitro
cultures. Following this, in 1983, the recombinant
plasmid containing human interleukin 2 (IL-2) cDNA was
identified in a cDNA library constructed from mRNA derived
from phytohemagglutinin and phorbol ester induced
splenocytes8 and from partially purified human
leukaemic T-cell line IL-2 mRNA.9 Eventually, in 1992, the
crystal structure of IL-2 was solved.10
In early preclinical studies, systemic administration of
IL-2 to nude mice induced specific T-helper cells, cytotoxic
cells and autoantibody production.11,12 It also
demonstrated an antitumor effect with IL-2 dependent
expansion of immune lymphocytes.13,14 Based on these
early preclinical studies and an understanding of interlukin
2 biology, the phase I trial was performed in 1985.
Ten patients with a variety of advanced stage malignancies
unresponsive to conventional treatments were
treated with at least 30 000 U/kg of IL-2 by bolus admin-
Keywords: interleukin 2, IL-2, biology, renal cell carcinoma, CD25,
T cells, immune response, toxicity, bempegaldesleukin, nivolumab,
NKTR-214,
Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr.,
Professor of Cancer Research, Professor and Chair ad interim, Department
of Genitourinary Medical Oncology, Division of Cancer Medicine,
MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374,
Houston, TX 77030-4009 Email: ntannir@mdanderson.org
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