Why do Coley's Tocins work against cancer?
One rationale argues that macrophages are either in "repair mode", furthering the growing of cancer, or in "defense mode", destroying cancer. However, macrophages are in "defense mode" only if there is some recognized enemy. As cancer tissue is not recognized as enemy (but as normal body tissue), there is a need to bring more macrophages into "defense mode" by simulating an infection. The simulated infection results in a real fever. Unlike hyperthermia, real fever not only means heating of the body but also higher activity of the immune system. Thus, fever is seen as a precondition for a therapy using Coley's Toxins to succeed.
http://en.wikipedia.org/wiki/Coley%27s_Toxins is updated regularly!!
Reader's comment:
I’ve seen the Wiki page.
Based on personal experience (including an antisense drug against glioblastoma, an antibody drug targeting the cobalamine (vitamin B12) receptor, a CTL therapeutic vaccine for prostate cancer, a chemotherapeutic drug for breast cancer, I came to the decision in 2003 that targeting cancer cells through genomics is, in the practical real-world sense, crap. Antisense probably won’t work but in any case can’t be delivered into the cells. Chemotherapy is poison. Antibodies help for a small segment of the population for 12-24 months at which time the individual becomes immunogenic, possibly because the antibodies are made from chimeric mice. I have a friend who is working on that problem by growing fully-human antibodies but that approach if it works will only impact a minority and it will be a very expensive drug (because the people who supply the money are driven by pure greed). CTL vaccines can also have some effect, but it is a weak effect (not curative) that does not persist and, because there are some 1000 human HLA types and the vaccine must be matched to HLA, this is also a very expensive approach (because the people who supply the money are driven by pure greed).
Here is what she commented on:
Deliberately provoking local inflammation drives tumors to become their own protective vaccine site
1. Connie Jackaman1, 2. Andrew M. Lew2, 3. Yifan Zhan2, 4. Jane E. Allan1, 5. Biljana Koloska3, 6. Peter T. Graham3, 7. Bruce W. S. Robinson1 and 8. Delia J. Nelson1,3 + Author Affiliations 1. 1School of Biomedical Sciences, Curtin University, Kent St Bentley, Perth, Western Australia 6102, Australia 2. 2School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia 6009, Australia 3. 3Walter and Eliza Hall Institute, Melbourne, Victoria 3050, Australia 1. Correspondence to: D. Nelson; E-mail: delianelson @ curtin.edu.au * Received June 20, 2008. * Accepted August 26, 2008.
Abstract
Anti-cancer immunotherapies aim to generate resolution of all existing tumors, including inaccessible ones, and provide long-term protection against recurrence. This is rarely achieved. Thus, we aimed to determine if the tumor microenvironment could be turned into a potent 'self'-vaccine site. Our target was to eradicate larger tumor burdens. Our models respond to single-agent immunotherapies; however, they fail at a precisely defined 'cut-off' tumor burden. Thus, this system was used to define the immune mechanisms required to mediate regression of larger tumors that are resistant to mono-immunotherapies. We report that direct injection of IL-2 with agonist anti-CD40 antibody into the tumor bed resulted in permanent resolution of treated and untreated distal tumors. Tumor-infiltrating CD8+ T cells and neutrophils collaborated to eradicate treated tumors, IFNγ was not critical and protective memory was preserved. This approach relied only on tumor antigens expressed within the tumor microenvironment. It also avoided systemic toxicities, did not require chemotherapy or surgery and is clinically useful because only one tumor site has to be accessible for treatment. We conclude that provoking intra-tumoral inflammation skews the tumor microenvironment from tumorigenic to immunogenic, resulting in the resolution of treated and untreated distal tumors, as well long-term protective memory.
Why Pfizer Can't Cure Cancer
Pfizer is pouring resources into new cancer drugs, but the results have been mediocre. Its most promising cancer drug in testing helps just 5% of lung cancer patients with a particular tumor mutation. Numerous Pfizer cancer trials in broader populations have fizzled. AstraZeneca and other drug companies aren't doing much better. Most new cancer drugs slow progress of the disease by just a few months.
Cancer geneticist Garth Anderson of Roswell Park Cancer Institute thinks he knows why so many cancer drugs are flopping.
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The theory behind targeted cancer drugs is simple: find the key gene mutations driving growth of tumors and then devise drugs that block those mutated proteins. This theory led to breakthrough drugs like Novartis' Gleevec for chronic myeloid leukemia and Roche's Herceptin for certain breast cancers.
The flaw in this logic, Anderson says, is that common tumors simply don't have a few key mutations that can be targeted. They have so much genetic damage that it may be impossible to safely destroy them with drug that hit just one or two bad genes. The problem, Anderson says, is something called genomic instability. Essentially, it means that tumors are mutating like crazy.
Most common tumors have innumerable gene mutations driving their growth—and that these mutations are changing all the time. In one study he did in 1999, he found 11,000 genetic changes in the DNA of colon tumors, indicating extensive DNA damage.
It gets worse: within a single large tumor, different cells may have different genetic mutations driving their growth, Anderson says. A drug that hits one of the mutations may shrink part of the tumor initially, but is doomed to fail in the long run—the rest of the tumor will just fill the gap. "It is like stepping on a jellyfish, you may hit part of it but it squirts out somewhere else," he says. "It is a nightmarish problem."
Anderson has been working on cancer genetics since 1971, when the idea of cancer-causing genes was new. "I told my parents that we will have this solved by 1980," he recalls. "The idea was that cancer is simple, a few bad genes, and we will go after them." He first realized that it was going to be far more difficult when data from his colon experiment was starting to roll in the mid 1990s. At breakfast at a conference in Italy, "we grabbed some napkins and came up with some numbers" for how many mutations each tumor cell would have." The numbers were colossal. It was like, 'oh sh-t, this is a different beast than we thought it was.'" More detailed data since then has confirmed his early work. A recent Genentech paper in Nature looked at 1507 genes from 441 tumors and found a colossal 2576 genetic mutations.
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Targeting bad genes will work in many less common cancers (such as chronic leukemia) that don't have massive genetic damage and are driven by just a few genetic changes. Drugs that boost the immune system against cancer, such the melanoma drug ipilimumab from Bristol-Myers Squibb, could also get around the many-gene-defects problem.
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The Pfizer Inc drug, crizotinib, shrank the tumors of 57 percent of patients and stabilized another 33 percent, Dr. Eunice Kwak of the Massachusetts General Hospital and colleagues reported in the New England Journal of Medicine.
... cancer pill that could help as many
as 5 percent of people with the most common type of lung cancer helps most patients treated but may be vulnerable to resistant tumors, researchers reported on Wednesday. oct2010
Existing cancer pills like AstraZeneca's Iressa and Roche's Tarceva are already known to be effective against cancer in patients with a mutation activating the epidermal growth factor receptor (EGFR).
Luis de la Cruz-Merinoa, Enrique Grande-Pulidob, Ana Albero-Tamarita, Manuel Eduardo Codes-Manuel de Villenaa
aMedical Oncology Department, Virgen de la Macarena University Hospital, Seville, Spain; bPfizer Medical Department, Madrid, Spain
Key Words. Cancer • Tumor-infiltrating lymphocytes • Immune tolerance • Cancer vaccines • CTLA-4 • GM-CSF • IL-2
Correspondence: Luis de la Cruz-Merino, M.D., Servicio de Oncología Médica, Hospital Universitario Virgen de la Macarena, Avenida Doctor Fedriani, 3, 41071 Sevilla, Spain. Telephone: 0034-955008934/955008932; Fax: 0034-954902219; e-mail: lucme12 ]at[ yahoo.es
Received August 1, 2008; accepted for publication October 28, 2008; first published online in THE ONCOLOGIST Express on December 4, 2008.
Disclosure: Employment/leadership position: Enrique Grande-Pulido, Pfizer Pharmaceuticals; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: None; Honoraria: None; Research funding/contracted research: None; Ownership interest: Enrique Grande-Pulido, Pfizer Pharmaceuticals; Expert testimony: None; Other: None.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.
Cancer may occur as a result of abnormal host immune system tolerance. Recent studies have confirmed the occurrence of spontaneous and induced antitumor immune responses expressed as the presence of tumor-infiltrating T cells in the tumor microenvironment in some cancer models. This finding has been recognized as a good prognostic factor in several types of tumors. Some chemotherapy agents, such as anthracyclines and gemcitabine, are effective boosters of the immune response through tumor-specific antigen overexpression after apoptotic tumor cell destruction. Other strategies, such as GM-CSF or interleukin-2, are pursued to increase immune cell availability in the tumor vicinity, and thus improve both antigen presentation and T-cell activation and proliferation. In addition, cytotoxic T lymphocyte antigen 4–blocking monoclonal antibodies enhance immune activity by prolonging T-cell activation. Strategies to stimulate the dormant immune system against tumors are varied and warrant further investigation of their applications to cancer therapy in the future.
Does that sound like they have a clear idea?
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