Mesothelioma Immunotherapy Treatment with Interferon
28.1 IMMUNOTHERAPY FOR MESOTHELIOMA
28.11 What are Interferons
Immunotherapy includes various investigational drugs to fight mesothelioma
including Interferons "Interferons are a class of natural
proteins produced by the cells of the immune systems of most animals in response
to challenges by foreign agents such as viruses, bacteria, parasites and tumor
cells. Interferons belong to the large class of glycoproteins known as
cytokines. (For discussion of the particular types of Interferon, see Wikepedia,
Interferon (1). There are three main types and 17 subtypes of
interferon. Interferons are proteins secreted by immune cells that
“interfere” with a virus’s ability to reproduce and proliferate.
Interferon has had some significant beneficial effect in treating mesothelioma
though significant side effects have been associated with Interferon. In
the laboratory, low concentrations of Interferon help boost the power of natural
killer T cells. With some tumors, interferons can help inhibit the
development of the blood vessels that tumors need to metastasize and grow, a
process called angiogenesis.
28.12 Rationale for Mesothelioma Immunotherapy
“The rationale for immunotherapy is the existence of immune abnormalities in
patients with MPM. Moreover, some human mesothelioma cell lines are
sensitive to cytokines like interferon -, -IFN, and interleukin 2, and to some
immune cells, which suggests that immunointervention would be beneficial.
Intrapleural administration of interleukin 2 has resulted in objective responses
in 19 to 55% of the cases in two trials including low numbers of patients in the
early stages of disease.” Monnert (1).
28.13 Studies with Interferon and Mesothelioma
One study reported a response rate for patients with stage 1 disease:
“Eighty-nine patients were included over 46 months. Eight histologically
confirmed complete responses and nine partial responses with at least a 50%
reduction in tumor size were obtained. The overall response rate was 20%. Most
responses were achieved in patients with early stage disease. The response rate
for patients with Stage I disease was 45%. Tolerance of interferon was good.
Treatment was performed on an outpatient basis. The main side effects were
hyperthermia, liver toxicity, neutropenia, and catheter-related infection.
CONCLUSIONS: Gamma- interferon is effective mainly in Stage I mesothelioma,
especially if the tumor is confined to the parietal or diaphragmatic pleura
(Stage IA).” Boutin (2)
However, a study at New York’s renowned Sloan Kettering reported, “The
combination of low-dose interferon alpha-2a and carboplatin did not result in
greater antitumor activity than that reported for single-agent carboplatin in
advanced malignant mesothelioma. Although toxicity was mild, carboplatin and
low-dose interferon, given at this dose and schedule, cannot be recommended for
this patient group.” O’Reilly (6).
28.13 Why Interferon Works
Another study reports how the related drug Interleukin works on laboratory
animals.
“Malignant mesothelioma appears to be sensitive to immunotherapeutic approaches,
and one of the most powerful immunomodulatory cytokines with antitumor effects
is interleukin (IL)-12. We have previously shown in a murine model of MM that
systemic administration of recombinant IL-12 induces a potent anti-MM immune
response. The nature and accessibility of MM tumors means that they are suitable
candidates for direct cytokine and gene-transfer therapeutic approaches. In
mixing experiments, paracrine IL-12 production inhibited growth of untransfected
MM cells provided that cells producing IL-12 represented more than 50-80% of the
inoculum.... This study shows that paracrine secretion of IL-12, generated by
gene transfer, can induce immunity against MM that can act locally and also at a
distant site. In addition, there was no evidence of toxicity, which has been
associated with the systemic administration of IL-12, indicating that this
cytokine is a good candidate for experimental gene therapy in MM.” Caminschi
(5).
28.14 Complimentary Effects of Inferon and Chemotherapy
Some suggest Interferon may compliment chemotherapy. Some studies have
reported increased survival with Interferon combined with chemotherapy. .
A Turkish study found moderately favorable results, a response rate of 24%
combining Interferon with Cisplatin. Metintas (14).
28.15 Cellular Studies of Interferon and Chemotherapy
Some cell studies support the hypothesis that Interferon can improve the
efficacy of chemotherapy. One study reported, “A combination of IF-alpha and
IF-gamma consistently augmented the response of the cell lines to methotrexate,
by as much as 75% for one cell line, although the response to the individual
IFNs was variable.” Hand (3).
28.17 Side Effects of Interferon
"Several different types of interferon are now approved for use
in humans, and interferon therapy is used (in combination with
chemotherapy and radiation) as a treatment for many cancers.
When used in the systemic therapy, IFN-α and IFN-γ are mostly
administered by an intramuscular injection. The injection of
interferons in the muscle, in the vein, or under skin is
generally well-tolerated. The most frequent side-effects are
flu-like symptoms: increased body temperature, feeling ill,
fatigue, headache, muscle pain, convulsion, dizziness, hair
thinning, and depression. Erythema, pain and hardness on the
spot of injection are also frequently observed. All known
effects are usually reversible and disappear a few days after
the therapy has been finished. HOwever, there are some serious
side effects and the patient is advised to read the accompanying
pamphlet." Wikepedia (1)
28.18 FDA Approval Status
"Interferon-alpha was approved by the United States
Food and Drug Administration (FDA) on
February 25,
1991
as a treatment for
hepatitis C. Several different forms of interferon alpha,
including interferon-alpha-2a, interferon-alpha-2b, and
interferon-alfacon-1 are approved for the treatment of viral
hepatitis. Interferon-alfa-2b is also used for
chronic myelogenous leukemia. Wikepedia (1)
Home page
References and Sources
1. Wikepedia, Interferon
Types of Interferon
"In humans, there are 3 major classes of interferon
(IFN):
1. The human type I IFNs consists of 13 different alpha isoforms (subtypes
with slightly different specificities) - IFNA(1,2,4,5,6,7,8,10,13,14,16,17,21),
and single beta - IFNB1, omega - IFNW1, epsilon - IFNE1 and kappa - IFNK
isoforms. Homologous molecules are found in many species, including rats and
mice (and most mammals) and have been identified in birds, reptiles, amphibians
and fish species. In addition to these IFNs, IFN zeta (limitin) in mice,IFN nu
in cats, IFN tau in ruminants and IFN delta in pigs have been identified. All
type I IFNs bind to a specific cell surface receptor complex known as IFNAR
consisting of IFNAR1 and IFNAR2 chains.
2. The type II IFNs consists of IFN gamma - IFNG, its sole member. The
mature IFNG ligand is an anti-parallel homodimer, and it binds to the IFNG
receptor (IFNGR) complex, which is made up of two of each IFNGR1 and IFNGR2
subunits.
3. The recently discovered 3rd class consists of IFN-lambda with 3 different
isoforms - IL29. IL28A, IL28B and signal through a receptor complex consisting
of IL10R2 and IFNLR1. "
2. Boutin, Intrapleural treatment with recombinant gamma-interferon in early
stage malignant pleural mesothelioma.Cancer 1994 Nov 1;74(9):2460-7.
3. Monnert, Intrapleural Infusion of Activated Macrophages and -Interferon in
Malignant Pleural Mesothelioma, Chest. 2002;121:1921-1927.
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