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‘To what extent is the combined use of ipilimumab and nivolumab in cancer treatment
viable?'
Introduction
Immunotherapy is ‘an innovative treatment approach that empowers the human immune
system to overcome cancer and other debilitating diseases’ (Fred Hutchinson Cancer
Research Center, 2015). Ipilimumab and nivolumab are types of monoclonal antibodies,
known by their brand names of Yervoy and Opdivo respectively. The US Food and Drug
Administration (FDA) approved Yervoy on 25th March 2011 (Yervoy (ipilimumab) FDA
Approval History, 2011) for treatment of late-stage melanoma. The FDA approved Opdivo
for advanced melanoma on 22nd December 2014, and then on the 4th March 2015, approved
use was expanded for treatment of lung cancer (Opdivo (nivolumab) FDA Approval History,
2015). It wasn’t until 22nd August 2011 (NHS Choices, 2011), that Yervoy was licensed for
late-stage melanoma in Europe by the European Commission, based on the advice of the
European Medicines Agency (EMA); Opdivo was licensed on 19th June 2015 for melanoma
patients (Bristol-Myers Squibb Newsroom, 2015). The global biopharmaceutical company
Bristol-Myers Squibb manufactures both of these immunotherapy drugs.
Brief History of Cancer Treatment
The ancient Egyptian trauma surgery textbook, Edwin Smith Papyrus, dated to around 3000
BC, holds the earliest description of cancer. Many cases of breast tumours or ulcers removed
by cauterization are noted, and the lack of treatment for this disease is highlighted. (American
Cancer Society, 2014)
Even then it was known that after being surgically removed, the cancer was likely to return.
Ancient physicians and surgeons found no curative treatment once cancer had spread,
believing that intervention, in the form of early and unsophisticated surgery, may result in
more harm, such as blood loss. However, there were major advances in general and cancer
surgery in the 19th and early 20th century, as well as the availability of anaesthesia in 1846.
William Stewart Halsted, professor of surgery at Johns Hopkins University, developed the
radical mastectomy in the late 19th century, which then became the basis of cancer surgery for
almost a century. However, clinical trials in the 1970s revealed that less extensive surgery
could be equally effective. The limitations of surgery were revealed as the understanding of
metastasis improved, allowing more refined treatments that removed minimal amounts of
normal tissue to be developed towards the end of the 20th Century. This depended on
improved oncology, surgical instruments and combining surgery with other treatments such
as chemotherapy and radiation. Now, modern surgery includes the use of new methods such
as fibre-optic technology, cryosurgery, laparoscopic surgery and radiofrequency ablation.
(ibid)
Hormone therapy was discovered in the 19th Century after Thomas Beatson discovered a
relationship between the ovaries and formation of milk in the breasts of rabbits. In 1878 he
removed the ovaries of rabbits and found that the production of milk was stopped.
Oophorectomy was then tested on advanced breast cancer patients, and often resulted in
improvement. The discovery of the stimulating effect of oestrogen on breast cancer provided
a foundation for hormone therapy, and has guided research into how hormones affect the
growth of cancer, in the hope of developing new drugs. (ibid)
1896 saw Roentgen presenting his new ‘X-ray’, winning the first ever Nobel Prize in physics
in 1901. Radiation therapy began shortly after, and in France, it was discovered that daily
doses of radiation over several weeks could improve a patient’s condition and their overall
chance for a cure. However, at the start of the 20th century it was discovered that it could also
be the cause of cancer; although advances in radiation physics and computer technology over
the remainder of this century made it possible to aim radiation more precisely. This can be
seen in therapies such as conformal radiation therapy (CRT), intensity-modulated radiation
therapy (IMRT) and intraoperative radiation therapy (IORT). (ibid)
The discovery of a compound called nitrogen mustard during World War II, which was
found to be effective against lymphoma, started the era of chemotherapy. This compound
acted as a model and triggered development of increasingly more effective alkylating agents
that damage the DNA of rapidly growing cancerous cells, destroying them. Today,
chemotherapy is improved and used in several ways, including new agents and delivery
techniques, such as monoclonal antibody therapy and liposomal therapy; improved ability to
overcome multi-drug resistance; and drugs that reduce side effects, such as anti-emetics. A
major discovery was the use of combination chemotherapy, instead of single agents. “Early in
the 20th century, only cancers small and localized enough to be completely removed by
surgery were curable. Later, radiation was used after surgery to control small tumor growths
that were not surgically removed. Finally, chemotherapy was added to destroy small tumor
growths that had spread beyond the reach of the surgeon and radiotherapist. Chemotherapy
used after surgery to destroy any remaining cancer cells in the body is called ‘adjuvant
therapy’.” (ibid)
Targeted therapies influence the processes controlling growth, division and spread, as well as
impacting the signals that cause natural death, of cancerous cells. These work in three main
ways: growth signal inhibitors, recognized in the 1960s; anti-angiogenesis agents, the concept
of which surfaced in the 1970s; and apoptosis-inducing drugs. (ibid)
Immunotherapy, the treatment category ipilimumab and nivolumab fall into, works by
mimicking natural signals used in the body to control cell growth, in other words, they
imitate or influence the immune response. This can be done directly, affecting cancerous cell
growth, or indirectly, aiding healthy cells in controlling the cancer. “One of the most exciting
applications of biologic therapy has come from identifying certain tumor targets, called
antigens, and aiming an antibody at these targets. This method was first used to find tumors
and diagnose cancer and more recently has been used to destroy cancer cells. Using
technology that was first developed during the 1970s, scientists can mass-produce
monoclonal antibodies that are specifically targeted to chemical components of cancer cells.
Refinements to these methods, using recombinant DNA technology, have improved the
effectiveness and decreased the side effects of these treatments” (ibid). In the late 1990s,
rituximab (Rituxan) and trastuzumab (Herceptin) were approved as the first therapeutic
monoclonal antibodies, used to treat lymphoma and breast cancer. Now, monoclonal
antibodies are often used in the treatment of specific cancers, and are at the forefront of
cancer research. (ibid)
Immunoglobulins
In general, antibodies have a symmetrical structure composed of a pair of identical
glycosylated heavy chains, and a pair of identical nonglycosylated light chains. Disulfide
bonds link these heavy chains, and the light chains are connected by a disulfide bond to one
heavy chain. This creates a basic subunit of two of each chain in a Y-shaped structure.
Immunoglobulins are proteins that have this general structure, without having known
antigen-binding properties. There are five different classes of immunoglobulins, each with
their own distinctive structural and biological features: IgM, IgD, IgG, IgE and IgA. The
immunoglobulin’s class depends on its heavy chain: M, D, G, E and A. (Goding, 1996)
Antibody genes exist in three groups: κ light chains, λ light chains, and heavy chains. In an
organism each group of genes lie on specific chromosomes, for example, in a mouse the κ
group can be found on chromosome 6, the λ genes on chromosome 16, and the heavy chain
group on chromosome 12. The genes for the variable region correlate to the genes of the
constant region. “The fact that the antibody gene rearrangements are orderly and monitored
by the cell for productive expression ensures that the great majority of cells express a single
allelic form of the heavy chain and a single allelic form of a single light chain type.” (ibid)
IgG, is the main immunoglobulin found in human blood, the second most abundant
circulating protein and contains long-term protective antibodies against numerous infectious
agents. There are four different types of IgG, again split into classes, in order of decreasing
abundance: IgG1, IgG2, IgG3, IgG4. Each sub-class has a slightly different function in terms
of the immune response, due to differences in their constant region (Immune Deficiency
Foundation, 2013); specifically their hinges and upper CH2 domains which are involved in
binding to IgG-Fc receptors and C1q, resulting in the sub-classes’ varied effector functions
(Vidarsson, Dekkers, and Rispens, 2014). For example, IgG1 and IgG3 subclasses are rich in
antibodies against proteins such as the toxins produced by the diphtheria and tetanus bacteria,
as well as antibodies against viral proteins. In contrast, IgG2 antibodies are predominantly
against the polysaccharide capsule of certain disease-producing bacteria (such as,
Streptococcus pneumoniae and Haemophilus influenzae) (ibid). “IgG molecules are able to
react with Fcγ receptors that are present on the surfaces of macrophages, neutrophils, natural
killer cells, and can activate the complement system. The binding of the Fc portion of IgG to
the receptor present on a phagocyte is a critical step in the opsonizing property IgG provides
to the immune response. Phagocytosis of particles coated with IgG antibodies is a vital
mechanism to cope with microorganisms. IgG is produced in a delayed response to an
infection and can be retained in the body for a long time. The longevity in serum makes IgG
most useful for passive immunization by transfer of this antibody.” (Immunoglobulin IgG
Class, 2014)
Ipilimumab is a fully human anti-CTLA-4 monoclonal antibody (IgG1κ) produced in Chinese
hamster ovary cells by recombinant DNA technology (YERVOY 5 mg/ml concentrate for
solution for infusion, 2015). “IgG1 comprises 60-65% of the total main subclass IgG, and is
predominantly responsible for the thymus mediated immune response against proteins and
polypeptide antigens. IgG1 binds to the Fc-receptor of phagocytic cells and can activate the
complement cascade via binding to C1 complex. IgG1 immune response can already be
measured in new borns and reaches its typical concentration in infancy. A deficiency in IgG1
isotype typically is a sign of a Hypogammaglobulinemia” (Immunoglobulin IgG Class,
2014). CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a protein receptor that,
functioning as an immune checkpoint, downregulates the immune system. CTLA4 is a
member of the immunoglobulin superfamily, found on the surface of Helper T cells, and acts
as an "off" switch when bound to CD80 or CD86 on the surface of antigen presenting cells by
transmitting an inhibitory signal to T cells. (Wikipedia: CTLA-4, 2015)
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), again
produced in Chinese hamster ovary cells by recombinant DNA technology (Nivolumab BMS
10 mg/mL concentrate for solution for infusion, 2015). “Comprising usually less than 4% of
total IgG, IgG4 does not bind to polysaccharides. Testing for IgG4 has been associated with
food allergies in the past and recent studies have shown that elevated serum levels of IgG4
are found in patients suffering from sclerosing pancreatitis, cholangitis and interstitial
pneumonia caused by infiltrating IgG4 positive plasma cells. The precise role of IgG4 is still
mostly unknown” (Immunoglobulin IgG Class, 2014). However, correlation between a relief
of symptoms and IgG4 induction in immunotherapy appears to be present. (Vidarsson,
Dekkers, and Rispens, 2014).
Antibody Mechanisms
There are a number of mechanisms by which antibodies may act; which mainly result in
stimulating and engaging other components of the immune system. They can simply block
the interactions of molecules, or be involved in more complex mechanisms, such as
activating the classical complement pathway (complement dependent cytotoxicity, CDC) by
interaction of C1q on the C1 complex with clustered antibodies. Antibodies may also act as a
link between antibody-mediated and cell-mediated immune response through engagement of
Fc receptors. (Antibody Effector functions, 2015)
Fc receptors (FcRs) are key immune regulatory receptors, connecting the humoral immune
response to cellular effector functions. Immunoglobulins have specific receptors, depending
on class: FcγR (IgG), FcεRI (IgE), FcαRI (IgA), FcμR (IgM) and FcδR (IgD). Human IgG
has three classes of receptor found on leukocytes: CD64 (FcγRI), CD32 (FcγRIIa, FcγRIIb
and FcγRIIc) and CD16 (FcγRIIIa and FcγRIIIb). FcγR1 is classes as a high affinity receptor,
nanomolar range KD, whereas the remaining receptors are low to intermediate affinity,
micromolar range KD. In antibody dependent cellular cytotoxicity (ADCC), FcvRs on the
surface of effector cells (including natural killer cells, macrophages, monocytes and
eosinophils) are able to bind to the Fc region of an IgG, which is bound to a target cell; a
signaling pathway is then triggered, resulting in the secretion of various substances, such as
lytic enzymes, perforin and tumour necrosis factor, which are involved in destroying the
target cell. The level of ADCC effector function varies for human IgG subtypes. This is
dependent on the allotype and specific FcvR, although the ADCC effector functions tend to
be high for IgG1 and IgG3, and low for IgG2 and IgG4. FcγRs bind to IgG asymmetrically
across the hinge and upper CH2 region; knowledge of this has lead to engineering efforts to
manipulate IgG effector functions. (ibid)
“The ability of antibodies to bind an almost unlimited number of target proteins with high
specificity always meant they were destined to be used as therapeutics. As early as 1900 Paul
Ehrlich coined the term ‘magic bullets’ in reference to antibodies.” (Antibodies as Tools,
2015)
This includes increasing effector functions through Fc engineering. Therapeutic antibodies
are mainly used in oncology, with over 200 antibodies passing through clinical testing. A
key mechanism of action for these antibodies is the targeted killing of cancerous cells
through encouragement and recruitment of the immune system, achieved through interactions
of the Fc domain with the complement component C1q or Fcγ receptors. Many therapeutic
antibodies resulted in unsuccessful clinical trials due to insufficient efficacy. In response to
this, efforts have been made to increase the potency of antibodies through enhancement of
their ability to mediate cellular cytotoxicity functions such as ADCC. There has also been a
specific focus on increasing the affinity of the Fc domain for the low affinity receptor
FcγIIIa. A number of mutations within the Fc region have been identified which enhance
binding of Fc receptors, either directly or indirectly, and significantly intensifying cellular
cytotoxicity. Focusing on the glycosylation of the Fc domain is an alternative approach; Fcγrs
interact with carbohydrates on the CH2 region, and the composition of these effects effector
function activity. An example of this includes afucosylated antibodies, which exhibit
substantially enhanced ADCC activity through increased binding to FcγRIIIa. (Fc
Engineering, 2015)
In contrast, Fc engineering can lead to decreasing effector functions. Circumstances exist in
which an antibody unable to activate specific effector functions is preferred. Usually IgG4
has often been used in these circumstances, but has fallen out of favour in recent years due to
its unique ability to undergo Fab-arm exchange, where heavy chains may be swapped
between IgG4 in vivo. Engineering approaches have determined key interaction sites for the
Fc domain with Fcγ receptors and C1q, before mutating these positions to decrease or prevent
binding. For example, through alanine scanning Duncan and Winter first isolated the site
covering the hinge and upper CH2 of the Fc domain, at which C1q binds. Researchers at
Genmab then identified mutants K322A, L234A and L235a, which are sufficient to almost
completely abolish FcγR and C1q binding, when used in combination. Modification of the
glycosylation on asparagine 297 of the Fc domain, known to be required for optimal FcR
interaction, can lead to a decrease in binding; as well as in enzymatically deglycosylated Fc
domains, recombinantly expressed antibodies in the presence of a glycosylation inhibitor and
the expression of Fc domains in bacteria. (ibid)
Futhermore, Fc engineering can enhance the serum half-life of IgG, which naturally persists
for an extended period in the serum due to FcRn-mediated recycling, resulting in a typical
half-life of approximately 21 days. There have been multiple efforts to engineer the pH
dependent interactions of the Fc domain with FcRn to increase affinity at pH 6.0 while
retaining minimal binding at pH 7.4. PDL BioPharma researchers identified the mutations
T250Q/M428L, resulting in an approximate 2-fold increase in IgG half-life in rhesus
monkeys. These enhancements are yet to be shown in humans, but significantly increased
half-lives may lead to a decrease in administration frequency, whilst maintaining or
improving efficacy. (ibid)
Mechanism of CTLA-4 and Ipilimumab
On the surface of T-cells, two proteins, CD28 and CTLA-4, play key roles in regulating
immune activation and tolerance. CD28 provides positive modulatory signals during the early
stages of an immune response; meanwhile, signals from CTLA-4 inhibit the activation of Tcells, particularly during strong T-cell responses. “CTLA-4 blockade using anti – CTLA-4
monoclonal antibody therapy has great appeal because suppression of inhibitory signals
results in the generation of an antitumour T-cell response” (Wolchok and Saenger, 2008)
A series of complex interactions is involved in the normal functioning of the immune system.
Tumours express antigens that can be recognized by the immune system, however, antigen
presentation alone is not sufficient to trigger an effective immune response to any
pathological entity, including cancer. T-cell activation is modulated by stimulatory signals
and inhibitory signals; CD28 provides positive signals whereas CTLA-4 provides negative
signals in the early stages, which work together to coordinate a response to a threat. CD28
initiates and maintains a T-cell response, partly through increase cytokine expressions
mediated by interaction with CD80 (B7-1) and CD86 (B7-2), its primary ligands, on the
surface of the antigen-presenting cell (APC). CTLA-4 essentially halts T-cell activation by
triggering an inhibitory signal. If CTLA-4 were to be inhibited, the immune system balance
would shift in favour of T cell activation, resulting in rejection of tumours by the host. (ibid)
Interactions between APCs and antitumour T-cells is key to developing antitumour T-cell
immunity, which is modulated through the influences of the competing stimulatory and
inhibitory molecules. The first signal in T cell activation is provided by the binding of the T
cell receptor (TCR) to its cognate antigen, however, a second stimulating signal is required
for T-cell proliferation. This signal is provided by CD28. CTLA-4 and CD28 are
homologous, and both found on the surface of T-cells, where they compete to bind to B7
costimulatory molecules on APCs. CTLA-4 has a significantly higher affinity for binding to
these molecules, giving CTLA-4 a competitive advantage over CD28. Not only are the roles
of these two proteins essential for the functioning of the immune system, but also determine
the fate of T-cells: activation or anergy. Preclinical studies have shown that CTLA-4 is
necessary to the downregulation of autoreactive and potentially destruction peripheral T-cell
responses; blockade of CD28 inhibits antitumour immunity whereas blockade of CTLA-4
stimulates antitumour immunity; and CD28 stimulates the production of cytokines, such as
interleukin-2 (IL-2) and upregulates antapoptotic genes, contrasting to the binding of CTLA4 to B7 molecules which results in inhibition of IL-2. It has been proposed that CTLA-4 not
only limits the body’s response to autoantigens, but also helps diversify the T-cell population,
meaning that during an immune response, T-cells specific to one epitope would not
necessarily dominate; therefore facilitating the targeting and destruction of pathogens. (ibid)
So how can T-cells proliferate and the immune system function at all when the affinity of
CTLA-4 for the B7 family of ligands is significantly greater than that of CD28, especially
noting that CTLA-4 is capable of forming a lattice of extensive and intricate protein
networks, effectively excluding CD28 and B7 ligands from interacting? There are several
details that allow CD28 an advantage over CTLA-4. For example, CD28 is expressed on the
surface of naïve and activated T-cells, and is present in 90% of CD4+ and 50% of CD8+ Tcells. In contrast, CTLA-4 expression is only induced by the activation of T-cells and its
upregulation reaches a maximum 2-3 days after the start of a response. Furthermore, CD28
localises to the T-cells plasma membrane, evenly distributed and intimately involved in any
T-cell and APC interactions, whereas CTLA-4 is located in the endosomal compartment,
where surface expression of this protein is highly restricted, which could be a regulatory
point for controlling its inhibitory influence. (ibid)
CTLA-4’s ability to inhibit the activation of any T-cell depends on numerous factors,
including the strength of the T-cell receptor (TCR) signal and the activation state of the APC.
CTLA-4 signals through an immunoreceptor tyrosine-based inhibitory motif to inhibit CD4+
and CD8+ T-cell responses. Research suggests that the localization of CTLA-4 to the
immunological synapse is preferred to conditions of stronger TCR signaling. Therefore
CTLA-4 is more likely to inhibit strong T-cell responses; this has significant implications for
the roles of CD28 and CTLA-4 in the coordination and regulation the T cell response to
antigens. “The preferential restriction of cells bearing higher affinity TCRs for any given
antigen may allow for greater representation of cells bearing lower affinity TCRs and thus
diversify the T-cell response to a threat. This diversified population of T cells may have
greater crossreactivity to similar antigenic epitopes and may be important in the development
of a protective T-cell response.” (ibid)
Data from preclinical and clinical trials show that anti-CTLA-4 monoclonal antibody therapy
results in direct activation of CD4+ and CD8+ effector cells; it does not considerably affect
the suppressive capacitiy of regulatory T-cells, meaning that CTLA-4 blockade does not
inhibit CD4+ nor CD25+ cells with the enhancement of effector T-cell activity secondary to
reduction in regulation. However, it does result in an altered ratio of effector cells to
regulatory cells within the tumour, with an increase in both CD4+ and CD8+ effector cells, in
mice. (ibid)
“Evidence from numerous studies indicates that CTLA-4 provides a braking mechanism on
T-cell activation and serves a critical role in immune response. CTLA-4 competes for the B7
family of ligands with CD28, a key costimulatory molecule that is essential for the effective
activation of T-cell–mediated immunity. CTLA-4 blockade results in enhanced antitumor
immunity, most likely through the direct activation of T cells. Anti–CTLA-4 monoclonal
antibody therapy, either as a monotherapy or in combination with a vaccine, may potentially
allow for a more specific immune response against tumor targets.” (ibid) Ipilimumab is a
CTLA-4 immune checkpoint inhibitor which blocks T-cell inhibitory signals induced by the
CTLA-4 pathway. This results in an increase in the population of reactive T-effector cells,
which mobilize to mount a direct T-cell immune attack against tumour cells. CTLA-4
blockade may also reduce the function of T-regulatory cells, contributing to an anti-tumour
response. Ipilimumab is capable of selectively depleting T-regulatory at the site of the
tumour, to increase the intratumoural T-effector/T-regulatory cell ratio, driving tumour cell
death. (YERVOY 5 mg/ml concentrate for solution for infusion, 2015)
Mechanism of PD-1 and Nivolumab
Evaluation of past immunotherapeutic approaches to treating cancer found limited success.
Increased understanding of the checkpoint signaling pathway involving the programmed
death 1 (PD-1) receptor and its ligands: PD-L1 (B7-H1) and PD-L2 (B7-DC), has clarified
the role of these approaches in tumour-induced immune suppression; this has led to critical
advancement in the development of immunotherapeutic drugs. (Dolan and Gupta, 2014)
The interaction between PD-1 and its ligand PD-L1/2, is a key pathway that is hijacked by
tumours in order to restrict immune control. Reversing the inhibition of adaptive immunity
can actively stimulate the immune system, utilizing antagonistic antibodies to block
checkpoint pathways, releasing tumour inhibition. These antibodies target CTLA-4, the PD-1
receptor and PD-L1 and facilitate antitumour activity. These agents are unique due to the
characteristic of targeting lymphocyte receptors or their ligands. (ibid)
PD-1 is an immunoinhibitory receptor, belonging to the CD28 family, and is expressed on Tcells, B-cells, monocytes, natural killer cells and many tumour-infiltrating lymphocytes
(TILs). PD-L1 is expressed on many cells including resting T-cells, B-cells and macrophages,
whereas PD-L2 expression is only found on macrophages and dendritic cells alone. Some
tumours may have a higher expression of PD-L1. These ligands inhibit T-cell proliferation,
cytokine production and cell adhesion. PD-L2 controls T-cell activation in lymphoid organs;
PD-L1 seems to decrease T-cell function in peripheral tissues. The induction of PD-1 on
activated T-cells takes place in response to the engagement of PD-L1/2, which limits effector
T-cell activity in peripheral organs and tissues during inflammation, preventing
autoimmunity; this is crucial in preventing tissue damage when the immune system is
responding to infection. An antitumour immune response may be triggered if this pathway is
blocked. The PD-1 pathway is similar to CTLA-4, in downregulating the response of T-cells
by overlapping signaling proteins that form part of the immune checkpoint pathway; they
function differently however, CTLA-4 concentrates on regulating the activation of T-cells,
whereas PD-1 regulates effector t-cell activity in peripheral tissues in response to infection or
the progression of a tumour. High levels of both of these molecules are expressed on
regulatory T-cells, which have shown to have immune inhibitory activity, essential for selftolerance. “The role of the PD-1 pathway in the interaction of tumour cells with the host
immune response and the PD-L1 tumour cell expression may provide the basis for enhancing
immune response through a blockade of this pathway. Drugs targeting the PD-1 pathway may
provide antitumor immunity, especially in PD-L1 positive tumours.”(ibid). Nivolumab, a
monoclonal antibody that binds to the PD-1 receptor, potentiates T-cell and antitumour
responses, via blockade of PD-1 binding to its ligands. This resulted in decreased tumour
growth in a study on mice. (Nivolumab BMS 10 mg/mL concentrate for solution for infusion,
2015)
Potential for the Combination of these Drugs
Preclinical evidence suggests that the roles of CTLA-4 and PD-1 in the regulation of adaptive
immunity are complementary, providing rationale for combing drugs that will target these
pathways. New data reveals that cytotoxic agents are able to antagonize immunosuppression
in the microenvironment of the tumour, promoting immunity based on the concept that
tumour cells die in multiple ways, and that some types of apoptosis can result in an enhanced
immune response. “For example, nivolumab was combined with ipilimumab in a phase 1 trial
of patients with advanced melanoma. The combination had a manageable safety profile and
produced clinical activity in the majority of patients, with rapid and deep tumour regression
seen in a large proportion of patients. Based on the results of this study, a phase 3 study is
being under- taken to evaluate whether this combination is better than nivolumab alone in
melanoma.” (Dolan and Gupta, 2014).
Clinical Trials
Since its development, many clinical trials have been designed to compare the use of antiCTLA-4 monotherapy, ipilimumab, with the combination therapy of ipilimumab and
nivolumab. Metastatic melanoma, metastatic renal cell carcinoma (MRCC) and small cell
lung cancer (SCLC) have been tested with the use of this immunotherapeutic approach.
Melanoma is a prototype of immunogenic tumour that has been known to respond to
immunotherapeutic approaches with interferon alfa and interleukin 2 (ibid). This has featured
in many clinical trials.
A double-blind study that involved 142 metastatic melanoma patients who had not previously
received treatment, was used to compare ipilimumab with ipilimumab and nivolumab.
Patients were assigned in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body
weight) combined with either nivolumab (1 mg per kilogram) or placebo, once every 3 weeks
for four doses. This was then followed by nivolumab (3 mg per kilogram) or placebo every
fortnight until the disease progressed or unacceptable toxic effects occurred. The primary end
point was the rate of investigator-assessed, confirmed objective response among patients with
BRAF V600 wild-type tumours. Among patients with BRAF wild-type tumours, the rate of
conformed objective response was 61% (44 of 72 patients) in the combination group versus
11% (4 of 37 patients) in the ipilimumab-monotherapy group (P<0.001). 16 patients (22%) of
the combination group reported complete responses versus none in the monotherapy group.
The median duration of response was not reached in either group and the median
progression-free survival was not reached with the combination therapy, but was 4.4 months
with monotherapy (hazard ratio associated with combination therapy compared with
monotherapy for disease progression or death, 0.40; 95% confidence interval [CI], 0.23 to
0.68; P<0.001). The response rate and progression-free survival results were similar for the
33 patients with BRAF mutation-positive tumours. The objective-response rate and
progression-free survival among advanced melanoma patients were significantly greater with
ipilimumab combined with nivolumab, rather than ipilimumab monotherapy. The
combination therapy had an acceptable safety profile. (Postow et al., 2015)
In a similar study, a 1:1:1 ratio was assigned to 945 previously untreated patients with
unrespectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or
ipilimumab alone. Progression-free survival and overall survival were co-primary end points.
The median progression-free survival was 11.5 months (95% CI, 8.9 to 16.7) with
combination therapy, compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab
monotherapy (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57;
P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab monotherapy (hazard ratio for
the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with
PD-L1 positive tumours, the median progression-free survival was 14.0 months in the
combined therapy group and in the nivolumab group; in patients with PD-L1 negative
tumours, progression-free survival was longer with combination therapy than with nivolumab
monotherapy (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to
7.1]). Among patients who had not previously been treated for metastatic melanoma,
nivolumab monotherapy or combination therapy resulted in significantly longer progressionfree survival than ipilimumab monotherapy. Patients with PD-L1 negative tumours responded
more effectively to combination therapy of PD-1 and CTLA-4 blockade than either agent
alone (Larkin et al., 2015). Dr James Larkin, a consultant at the Royal Marsden hospital and
one of the UK’s lead investigators, told the BBC: “For immunotherapies, we’ve never seen
tumour shrinkage rates over 50% so that’s very significant to see. This is a treatment
modality that I think is going to have a big future for the treatment of cancer.” (The Guardian,
2015)
Similar to melanoma, kidney cancer has also been a prototype of immunogenic tumour that
responds to immunotherapy (Dolan and Gupta, 2014).
A Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell
carcinoma (MRCC) took place where patients were randomly split into two groups. In one
group of 21 patients, they received 3mg/kg of nivolumab and 1mg/kg of ipilimumab (arm N3
+I1); in the other of 23 patients, they received 1mg/kg of nivolumab and 3mg/kg (arm
N1+I3). This was administered intravenously every three weeks for four doses, and then
followed by 3mg/kg of nivolumab every fortnight until progression (protocol-defined that
post-progression treatment was allowed). The primary objective was to assess safety; the
secondary objective was to assess efficacy. 80% of patients (35 in total, 17 in N3+I1, 18 in
N1+I3) had prior systemic therapy. Objective response rate was 43% (N3+I1) and 48%
(N1+I3). The median duration of response was 31.1 weeks (7 ongoing) in N3+I1 and not
reached (9 ongoing) in N1+13. Responses occurred by the first tumour assessment (week 6)
in 44% of patient in the N3+I1 arm and in 55% of patients in the N1+I3 arm. Stable disease
as the best overall response was seen in 5 (24%; N3+I1) and 8 (35%; N1+I3) patients.
Nivolumab and ipilimumab showed an acceptable safety profile and encouraging antitumour
activity in MRCC, with most responses ongoing. Studies are ongoing to explore this
combination in a Phase III trial. (Hammers et al., 2014)
There is also an ongoing trial comparing the combination of nivolumab and ipilimumab with
sunitinib (another biological therapy, also known as Sutent). The aims of this trial are to see
the efficiacy of nivolumab and ipilimumab in renal cell cancer and to see any possible side
effects. (A trial of nivolumab combined with ipilimumab for kidney cancer (CA209214),
2015)
A Phase I/II study of nivolumab with or without ipilimumab for the treatment of recurrent
small cell lung cancer (SCLC) hoped to see improvement in patients who had responded well
to initial platinum (PLT) based chemotherapy (CT), but the disease had rapidly progressed
afterwards. Combined blockade of PD-1 and CTLA-4 immune checkpoint pathways was
known to have a manageable safety profile with anti-tumour activity. Patients who were PLT
sensitive or refractory and had progressive disease were enrolled regardless of tumour PD-L1
status or the number of prior CT regimens. Patients were randomised to a group that
administered 3mg/kg of nivolumab intravenously every fortnight, or to other groups that
involved administration of 1mg/kg of nivolumab and 1mg/kg of ipilimumab, 1mg/kg of
nivolumab and 3mg/kg of ipilimumab or 3mg/kg of nivolumab, intravenously every 3 weeks.
These treatments lasted for four cycles and were followed by 3 mg/kg of nivolumab every
fortnight. The primary objective was the overall response rate. Other objective included
safety, progression-free survival, observational study and biomarker analysis. 75 patients
were enrolled (40 into the nivolumab monotherapy group, 35 into the combination therapy
groups) of which 59% had less than or equal to 2 prior regimens. Of the 40 evaluable
monotherapy patients, partial responses was seen in 6 (15%), the duration of ongoing
responses was 80-251+ days; stable disease occurred in 9 (22.5%); and progressive disease in
25 (62.5%). In the 20 evaluable combined therapy patients, 1 had a complete response (5%),
the duration of response was 322+ days; 4 had a partial response (20%), duration of response
was 41-83+ days); 6 experienced stable disease (30%); and 9 had progressive disease (45%).
In the combined group, 12 patients had not reached the first tumour assessment and 3 were
not evaluable. 9 patients (23%) have continued treatment with nivolumab monotherapy and
19 (54%) have continued the combined therapy. In this PD-L1 unselected SCLC population
with progression post-PLT, nivolumab alone or combined with ipilimumab was tolerable.
Overall response rate was 15% (nivolumab) and 25% (nivolumab and ipilimumab) for
evaluable patients; durable responses were noted. (Antonia et al., 2015)
An ongoing trial is taking place of nivolumab and ipilimumab for people with solid tumours
that have spread and have most recently recruited patients with SCLC. The aims of this trial
are to compare nivolumab monotherapy with combined therapy and to test the safety of this
treatment. (A trial of nivolumab and ipilimumab for people with solid tumours that have
spread (CA209032), 2015)
Adverse Reactions
Perhaps one of the most important disadvantages of any medical treatment is the side effects.
As individual drugs, both ipilimumab and nivolumab have many adverse reactions.
Ipilimumab has some mild to moderate effects such as moderate diarrhoea or colitis, adverse
reactions in the endocrine glands such as hypophysitis, and unexplained motor neuropathy or
muscle weakness. More severe or life-threatening effects include gastrointestinal
haemorrhage, symptoms of hepatotoxicity, severe motor neuropathy, pancreatitis and toxic
epidermal necrolysis. In a clinical trial of around 10,000 patients to evaluate its use with
various doses and types of tumours, therapy was discontinued for adverse reactions in 10% of
patients (YERVOY 5 mg/ml concentrate for solution for infusion, 2015).
Immunotherapy with ipilimumab is associated with inflammatory adverse reactions resulting
from increased immune activity (known as immune-related adverse reactions), which is
likely to be related to its mechanism of action. Most of these surface during the induction
period of therapy, although some reactions appear months after the final dose. Lifethreatening complications can be minimised with early diagnosis and appropriate
management. Systemic high-dose coriticosteroid may be required for managing severe
immune-related adverse reactions, although use at baseline, before starting ipilimumab,
should be avoided due to the risk of potential interference with pharmacodynamic activity
and efficacy; it does not appear to affect efficacy after treatment has commenced (ibid).
As a response to any adverse reactions, there are four main levels of action. First, the dose of
ipilimumab is withheld until the reaction resolves to Grade 1, 0 or returns to baseline; then, if
resolution occurs, therapy is resumed. However, in response to no resolution, doses continue
to be withheld until reaction resolves before continuing therapy. Discontinued use of
ipilimumab is implemented if a resolution to Grade 1, 0 or baseline is not reached (ibid).
In clinical trials of patients with unresectable or metastatic melanoma, the most common
adverse reactions associated with ipilimumab 3 mg/kg in 5% or more patients were fatigue,
diarrhoea, pruritus, rash and colitis. 11 of 1,024 evaluable patients tested positive for binding
antibodies in an electrochemiluminescent (ECL)-based assay. However, infusion-related or
peri-infusional reactions that correspond with hypersensitivity or anaphylaxis were not
reported in these patients; neutralising antibodies against ipilimumab were not detected.
(Fellner, 2012)
Ipilimumab is not recommended for use during pregnancy, because there is no data and the
potential risk of treatment to the developing foetus is currently unknown. However, animal
reproductions studies have shown reproductive toxicity and it is known that human IgG1
crosses the placental barrier. It should only be considered if the clinical benefit outweighs the
risk (YERVOY 5 mg/ml concentrate for solution for infusion, 2015). Ipilimumab has been
shown to be present at low levels of concentration in milk from cynomolgus monkeys that
were treated during pregnancy. It is not known if it is secreted in human milk, although
secretion of IgGs is generally limited in breast milk. No effects are anticipated for
systemically breastfed infants, although due to the potential risk, a decision must be made as
to whether to continue or discontinue breastfeeding or Yervoy treatment, balancing the
benefits of breastfeeding for the child and of the therapy for the woman. Studies evaluating
the effect on fertility have not been carried out and so are currently unknown (ibid).
Yervoy has a minor influence on the ability to operate machinery and to drive due to
potential side effects such as fatigue. Therefore, patients should be advised to use caution
when carrying out these activities, until they are sure that ipilimumab does not adversely
impact them (ibid).
Nivolumab is also associated with immune-related adverse reactions, and patients should be
carefully monitored at least up to 5 months after the last dose. If any severe or lifethreatening adverse reactions occur, use of Opdivo must be permanently discontinued. The
most frequent adverse reactions in two studies of squamous non-small cell lung cancer
(NSCLC) reported in more than 10% of patients, included fatigue, decreased appetite and
nausea. The majority of these reactions were mild to moderate (Nivolumab BMS 10 mg/mL
concentrate for solution for infusion, 2015). Many of the side effects experienced are similar
to those seen in ipilimumab.
In the event of moderate to severe immune-related adverse reactions, nivolumab should be
withheld and the administration of corticosteroids should commence. A taper of at least one
month must be respected upon improvement before recommencing therapy, if not reactions
may worsen rapidly. If no improvement occurs, non-corticosteroid immunosuppressive
therapy should be used. Opdivo should not be resumed while the patient is receiving either of
these alternatives (ibid).
Similar to ipilimumab, little or no data is available regarding use during pregnancy, breastfeeding and effect on fertility. Therefore risk to infants cannot be excluded and nivolumab
should only be used in exceptional circumstances where the benefit outweighs the risk.
Additionally, effective contraception should be used for at least 5 months after the last dose,
to ensure the risk is minimised (ibid).
Operating machinery and driving should also be treated in the same way as ipilimumab
(ibid).
Some adverse effects regarding the combined therapy of these drugs have been seen in the
results of clinical trials. A comparison of combined therapy and ipilimumab monotherapy
found that drug-related adverse events of grade 3 or 4 were reported in 54% of patients who
received combined therapy, and only 24% in the monotherapy group. Most of these events
were resolved with immune-modulating medication (Postow et al., 2015). Another trial,
comparing combined therapy to ipilimumab monotherapy and nivolumab monotherapy,
found that adverse reactions of grade 3 or 4 occurred in 16.3% of the patients in the
nivolumab group, 55% of the combined group and 27.3% of the ipilimumab group (Larkin et
al., 2015). On one trial looking at nivolumab monotherapy or combined therapy in SCLC,
one patient experienced myasthenia gravis during the study, which was fatal (Antonia et al.,
2015).
All cancer treatments may result in side effects. For example, chemotherapy, using a drug
such as doxorubicin, may also damage normal cells as well as cancerous cells. These can
include flu-like symptoms and a high temperature of over 38°C (can be signs of infection),
hair loss, vomiting, diarrhoea and difficulty with breathing (Royal Marsden, 2014).
Use of doxorubicin can also have serious effects on cardiac muscle, which could be
devastating (Doxorubicin hydrochloride 2mg/ml solution for infusion - Summary of Product
Characteristics (SPC) - (eMC), 2014). Sunitinab (Sutent), another biological therapy
mentioned earlier for experimental use in combination with ipilimumab and nivolumab in an
ongoing trial, also can have severe adverse reactions including renal failure, anaemia, fatigue,
diarrhoea and hypertension. Sudden death and multi-system organ failure also had a possible
link to this treatment (SUTENT 12.5mg, 25mg, 37.5mg and 50mg Hard Capsules - Summary
of Product Characteristics (SPC) - (eMC), 2015).
Cost of Treatment
Immunotherapy drugs, though effective, come with a hefty price tag. Ipilimumab was
approved by the National Institute for Health and Care Excellence (NICE) in December
2012, despite its high cost of approximately £75,000 for a four-dose treatment course, as
Bristol-Myers Squibb agreed on an acceptable discount for the Department of Health (The
Guardian, 2015), after previously being denied in 2011 as the long-term benefits were unclear
and the cost too high for the NHS (Fellner, 2012). Pharmaceutical companies can make
enormous profits by controlling knowledge of drug manufacture, and as the market of
immunotherapy treatments has been estimated to be worth up to £26bn a year in sales (The
Guardian, 2015), this has become the new focus. The price of the combined treatment is
likely to be much higher than this figure, due to the use of the two drugs, ipilimumab and
nivolumab.
This can put pressure on health systems all over the world, as well as richer economies like
the UK, because there are huge differences in cost; the British Generic Manufacturers
Association says "The average cost to the NHS of a generic medicine is £3.79, whilst the
average cost of a branded medicine is £19.73." The huge profit is the reward, funding and
incentive for the research and development of new drugs (The Guardian, 2014). But retail
prices aren’t reflective of the production costs, which are a tiny fraction of the overall price
tag; they are “set according to the maximum amount that a market will bear in the absence of
price-lowering competition” (ibid).
However, all cancer treatment comes at a cost. As said by Dr Annabel Bentley, medical
director of Bupa Health and Wellbeing, "A single course of chemotherapy for cancer can cost
between £25,000 and £30,000, and someone may need several courses” (The Telegraph,
2011). An average six-week cycle of Sutent costs around £3,139 and Pfizer, the
manufacturer, provides the first cycle of treatment to NHS patients for free (The Telegraph,
2009). A herceptin-style drug called Kadcyla (trastuzumab emtansine), manufactured by
Roche, that had the ability to offer some advanced breast cancer patients nearly 6 months of
extra life was turned down for use in the NHS in 2014, for its high price of £90,000 per
patient. However it is being funded through the special Cancer Drugs Fund, “We are very
aware of the importance that people place on life-extending cancer drugs and a decision not
to recommend a cancer treatment for routine NHS funding is never taken lightly.” (The
Guardian, 2014)
Conclusion
Immunotherapy has unsurprisingly become the forefront of cancer research in recent years
(American Cancer Society, 2014). It has shown real promise of improving the lives of many
cancer patients, including complete responses.
The mechanism of this therapy, effectively ‘rewiring’ the immune system to create an antitumour response, is innovative and the use of antibodies which are able to bind to specific
target proteins with high specificity, means their application in oncology is obvious
(Antibodies as Tools, 2015).
The new combined therapy of ipilimumab and nivolumab has shown encouraging results in
clinical trials, including tumour shrinkage rates of over 50% that have never been seen before
(The Guardian, 2015). This is an incredible feat, worked on by oncologists and researchers
for thousands of years, since before the ancient Edwin Smith Papyrus, when there was almost
no treatment for cancer (American Cancer Society, 2014). In one trial, the median
progression-free survival was increased by 8.6 months by combined therapy instead of
ipilimumab monotherapy (Larkin et al., 2015). These results are extremely exciting for the
medical industry and there are increasing numbers of ongoing clinical trials, researching the
effects this therapy will have on different types of cancers, including metastatic melanoma,
renal cell carcinoma and small cell lung cancer. There is potential of this therapy being able
to treat a diverse range of cancers, and therefore improve the lives of millions of patients.
Although there are cases of increased adverse reactions in the combined therapy, including a
30% increase in a trial comparing monotherapy and combined therapy (Postow et al., 2015), I
believe that the benefit far outweighs the risk. For many patients, if they received
monotherapy or no treatment at all, their most realistic median-progression free survival was
just 2.9 months (Larkin et al., 2015), and many mortalities would have occurred much
sooner. In some cases, patients were able to make a full recovery, seen in a clinical trial
comparing ipilimumab monotherapy with combined therapy where 22% of the combination
group reported complete responses versus none in the monotherapy group (Postow et al.,
2015).
In addition to this, all cancer treatments have adverse reactions, such as flu-like symptoms in
chemotherapy (Royal Marsden, 2014), and renal failure using Sunitinab (SUTENT 12.5mg,
25mg, 37.5mg and 50mg Hard Capsules - Summary of Product Characteristics (SPC) (eMC), 2015). If the results of this combined therapy are more promising than existing
treatments, which in the case of ongoing trials look optimistic (The Guardian, 2015), then a
similar risk of adverse reactions is a small compromise that patients and professionals alike
may be willing to make.
The high price of this treatment has caused many to question its economic viability,
especially during this economic climate, where there is already strain on the NHS in the UK.
Its high price reflects the results of the therapy, but also comfortably profits the
pharmaceutical companies (The Guardian, 2014). However, all cancer treatment will come at
a cost. It raises an important but difficult ethical question – how much is a human life worth?
In reality it is impossible to fund numerous treatments for every disease; the most costeffective treatments must be funded, without compromising the health of the population. The
most difficult part is finding out which treatments these are, ongoing clinical trials will help
provide evidence for making these important decisions. In my opinion, if the combined
therapy of ipilimumab and nivolumab can significantly improve patients’ health on a variety
of different cancers, it would be a viable option. If not however, efforts may be better off
invested in developing a more cost-effective alternative.
After all my research that I’ve carried out in respect to the combined therapy of ipilimumab
and nivolumab, I believe that it is an extremely promising and exciting example of
immunotherapy, hence it’s high price tag. The fact that it is such a current topic, with new
resources being published constantly, means that it is hard to make an absolute, wellinformed decision about it viability. More evidence needs to be produced to back up the use
of this treatment before it can be deemed as completely viable, however, this combined
therapy has certainly had an enthusiastic introduction into the medical industry.
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