Introduction
Cancer is one of the major health problems worldwide (Siegel, Miller &
Jemal, 2019). Each year the number of cancer cases and associated deaths
increases worldwide. Nonetheless, despite the increase in cancer
incidence over the past 30 years, the number of deaths has fallen short
of the estimated values. Several milestones in cancer therapy are at the
origin of the steadily increasing survival rates, and of particular
interest are the interleukin 2 (IL-2)-based immunotherapy regimens
(DeVita & Rosenberg, 2012).
Immunotherapy was recently added as a major cancer treatment approach,
along with surgery, radiotherapy, and chemotherapy. In the early 1960s,
it became evident that the immune system was able to prevent the onset
of several cancers, as pointed out by some ground-breaking experiments
(Brondz, 1964; Granger & Weiser, 1964; Hellstrom, Hellstrom, Pierce &
Bill, 1968). The discovery of the T cell growth factor in 1976, later
renamed IL-2, further stimulated the studies of the immune response of
lymphocytes to cancer cells. The seminal work of Rosenberg et al .
(Rosenberg et al., 1985) showed that immune modulation could be used to
cause the regression of invasive metastases in patients suffering from
various types of cancers, including malignant melanoma, colorectal
cancer, sarcoma, renal cell cancer adenocarcinoma and oesophageal
cancer. This led to the approval of IL-2 for the treatment of renal
carcinoma and metastatic melanoma in 1992 and 1998, respectively (Jiang,
Zhou & Ren, 2016).
The notion that the immune system could play an important role in cancer
treatment led to the development of new antibodies for use as
immunomodulatory agents. Patients treated with ipilimumab or rituximab,
two monoclonal antibodies designed to promote the immune system response
against melanoma and lymphoma, respectively, showed an improvement in
overall survival(Hodi et al., 2010; Molina, 2008). These rates increase
significantly when these immunomodulators are used in combination with
conventional chemotherapeutic regimens (Castro, Sandoval-Sus, Bole,
Rassenti & Kipps, 2008) and other immunomodulators (Shanafelt et al.,
2019).
The first application of immunomodulators in cancer therapy was the use
of IL-2 and interferon-α (IFN-α). IL-2, as mentioned above, was first
used in the treatment of metastatic melanoma in 1984. In this pioneering
work, one patient was treated with a high dose of Escherichia
coli -derived recombinant human IL-2 (rhIL-2). Within two months, all
tumours showed extensive necrosis, and were completely eliminated a few
months later (Rosenberg, 2014). Following this success, 409 patients
with metastatic melanoma and metastatic renal cancer were subject to
high dose rhIL-2 regimens. Complete regression was observed in 7% of
the melanoma and 9% of the renal carcinoma cases, granting this therapy
its approval by the FDA (McDermott & Atkins, 2006). However, it became
clear that IL-2 alone was not enough to improve patient survival(Jiang,
Zhou & Ren, 2016). Nevertheless, rhIL-2 is currently used, either alone
or in combination with other therapeutic agents, in the treatment of a
variety of malignancies that include melanoma and renal carcinoma,
leukaemia, neuroblastoma and non-small cell lung cancer (Mortara, Balza,
Bruno, Poggi, Orecchia & Carnemolla, 2018).
IFN-α, first approved for clinical use in the US in 1986, is another
cytokine widely used in cancer treatment. Recombinant human IFN-α type
2b (rhIFN-α2b) is used as a monotherapy or in combination with
antineoplastic drugs (Asmana Ningrum, 2014). Like other cytokines,
interferons display pleomorphic activities. In the case of IFN-α2b, the
anti-cancer activity can be divided into direct and indirect effects.
Cancer cell growth is inhibited directly by the induction of cell cycle
arrest and apoptosis(Gutterman, 1994). On the other hand, type I
interferons, such as IFN-α, have multiple effects on the overall state
of the immune system, promoting its activity against cancer
cells(Gutterman et al., 1980; Tompkins, 1999).
These discoveries led to the development of new treatments based on the
immune system potential to fight cancer. The field of immuno-oncology
grew significantly in the last 30 years and today it can be divided into
two major strategies: passive and active immunotherapy. Passive
immunotherapy comprises the use of antibodies or immunomodulatory
molecules, as well as the adoptive transfer of activated immune cells.
This last approach includes the isolation and expansion of patient
lymphocyte-activated killer (LAK) cells that are primed ex vivowith IL-2 to increase their anti-tumour activities (Nagasawa et al.,
2012). This ex vivo priming of lymphocytes results in a
population of highly active T cells that can be expanded and then
reinfused back into the patient, with significant results in tumour
regression (Nagasawa et al., 2012; Tsurushima et al., 1999), and have
also been used in a few trials with somewhat encouraging results
(Quattrocchi et al., 1999). The concept of isolating tumour-infiltrating
lymphocytes (TIL) or circulating T cells for in vitrocultivation, activation and expansion, and subsequent reinfusion, has
demonstrated promising results in the treatment of several malignancies,
supporting the therapeutic potential of tumour-specific T cells (Sharpe
& Mount, 2015). However, TIL isolation requires surgical techniques
that may not be possible in patients with visceral tumours in later
stages (Fan, Shang, Han, Song, Chen & Yang, 2018), and TAA recognition
is MHC-restricted. This means that the anti-tumour activity is only
developed against cells presenting foreign antigens bound to MHC
molecules. As tumours use immune escape mechanisms based on MHC
expression alteration and TAA processing, a fair part of these adoptive
cell transfer (ACT) therapies fail to produce significant results. To
overcome these problems, genetically engineered T cells have emerged as
an alternative (Fousek & Ahmed, 2015).
The branch of active immunotherapy comprises the methodologies that aim
to induce a response by stimulating the immune system. This differs from
the passive immunotherapy as the molecules/cells used in this case are
not produced by the host. In active immunotherapy the immune system is
boosted, with either cytokines, immunoadjuvants, or vaccines, to elicit
generic or specific responses (Baxter, 2014).
All these techniques have been proven effective in cancer treatment.
However, none of these is free from pitfalls. All the immunotherapy
regimens currently approved or under study perform extremely well in
some cancers and patients but fail completely in others. This was
observed early in the immuno-oncology era with IL-2-based treatments
that have a response of only ca . 7% (Rosenberg et al., 1985).
One drawback is the fact that some patients present little or no immune
response to their tumours, with the tumour microenvironment being devoid
of infiltrating lymphocytes, rendering cytokine-, antibody-, CTL- and
TIL-based therapies useless. This is nowadays recognised as the next big
challenge in cancer immunotherapy (Gajewski, 2015).
It is important to mention the economic impact of the available
treatments per patient. The cost of standard treatment with one
checkpoint inhibitor antibody is around \euro100 000 per year
(Fellner, 2012), while a single CAR-T treatment can reach \euro430 000
(Hay & Cheung, 2019). For these reasons, new cost-effective
immuno-oncology treatments are necessary to increase the number of
patients receiving such regimens and their efficacy. Many authors have
focused recently on a subset of lymphocytes – natural killer (NK) cells
– that possess the innate ability to detect transformed cells,
proposing them as the next “major target in cancer immunotherapy”
(Lorenzo-Herrero, Lopez-Soto, Sordo-Bahamonde, Gonzalez-Rodriguez,
Vitale & Gonzalez, 2018; Souza-Fonseca-Guimarães, Cursons &
Huntington, 2019).