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)
 

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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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