One in two Americans will be diagnosed with cancer at some point in their lives. Traditional options for treating these patients usually involve surgery, chemotherapy, and/or radiation therapy. The goal of these modalities is to destroy or remove the cancer cells. However, the limitation of these therapies is that they are highly-toxic or invasive and as a result the side effects can be debilitating. A relatively new approach to improve cancer treatment involves engaging the body’s immune system to recognize and destroy the cancer cells; this biological approach is termed immunotherapy.
To date, a common and somewhat successful approach to immunotherapy has involved the use of monoclonal antibodies (mAb). In this type of therapy, donor antibodies are injected into a vein and go on to attach to specific antigens, some attach to cancer cells and others to cells that help tumors grow. However, one limitation of this approach is that tumor specific antigens are often intracellular and therefore out of reach of the humoral immune response. To overcome this issue an alternative or complimentary therapy is required.
The concept of lymphocyte immunotherapy was assisted by the evolution of organ transplantation. In transplant recipients, graft-versus-host disease (GVHD), where the transplant T-cells attack host tissue, is an undesirable complication. However, some leukemia and lymphoma patients who experience mild GVHD have a demonstrated a decreased risk of recurrent cancer. In these cases it appears that the transplant cells reject the cancer cells of the host. This concept helped to generate the idea of utilizing immuno-competent donor T-cells to treat cancer patients.
The use of monoclonal T-cells or T-cell receptors (mTCRs) is being investigated as viable approach. This is based on the ability of lymphocyte receptors to recognize peptide or major histamine complex (MHC) molecules in tumor cells. As with mAb therapy, a key challenge is to generate a therapeutic response that has high specificity for the tumor cells so that normal tissue is not destroyed. One significant study found effective results when CD4+ T cells, together with CD8+ T cells, and interleukin-2 (IL-2) were transferred to melanoma patients. T-cells proliferated and attacked tumor cells and there was significant regression of the metastatic melanoma in 6 of the 13 patients.
Immunotherapy does not come without side effects. Thankfully, they are often considered mild compared to chemotherapy. Five patients in the aforementioned study exhibited onset of antimelanocyte autoimmunity. Four of these patients developed vitiligo and one developed uveitis. Vitiligo is a condition where the melanocytes are destroyed and skin pigmentation is lost on patches of the skin. Uveitis is inflammation of the interior eye that can result in blindness. Presence of these side effects indicates that although there are benefits, the treatment needs to be refined. Although immunotherapy is still in the early stages of development, great advancements have been made in the last decade. It will be interesting to see what the future holds.
References:
1. Davis ID, Jefford M, Parente P, Cebon J. Rational approaches to human cancer immunotherapy. J Leukoc Biol 2003;73:3-29.
2. Dudley ME, Wunderlick JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850-4.
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7 comments:
If a patient who receives treatment responds to the treatment but then relapses, is the say treatment option still available? In other words, will the donor cells be recognized as foreign by the host's cells upon secondary exposure? Also, I've heard that high levels of IL-2 has toxic effects... are people looking into using another cyokine in the IL-2 family but without the toxicity? This method of treatment seems to assume that the cancerous cells have a specific mutation that CAN be recognized by donor immune cells. Do you think cancers caused by overexpression of a wild type protein (for example: HoxC8 in prostate cancer) can utilize the same treatment regime?
It is fascinating how we are begging to be able to treat cancer not by fire bombing the whole body but by specifically targeting the troublesome cells in question. Even radiation therapy is starting to be modified in the way it's applied in order to try and target only the cancer. I specifically saw one treatment that uses radioactive beads about the size of a human hair that are implanted into the hepatic artery to specifically target liver cancer. Also, current work in cancer vaccines is also very promising.
Using activated T cells to treat blood cancers is a very cool idea, I completely agree; but what about solid tumors?
Also, according to the SEER at NCI, the incidence of all types of cancer in all types of people in the U.S. from 1974-2004, adjusted to 2000 census numbers, is about 460 per 100,000 or about 0.5%: not even close to 1 in 2. There is also a link on the SEER site to a paper with a very detailed explaination of how lifetime incidence rates should be calculated.
Jennyp, thanks for the comment. Your questions open the door to a larger issue in immunotherapy as it relates to how it should be applied. First let's address the issue of relapse and secondary exposure. Recent developments in molecular engineering techniques have enabled the creation of mAbs that have reduced immunogenicity, thus allowing for multiple treatments. The second issue you raise is also true. High-doses of IL-2 can generate exceptional results yet in many cases can be extremely toxic. Davis et. al. suggest that this is a result of the IL-2 development and studies being improperly modeled after chemotherapy. They go on to suggest that the proper model, now that the biology is better understood, is one where immunotherapy is considered an adjuvant therapy that may be used to control cancer as a chronic disease. Along this line the use of low-dose IL-2 to increase the efficacy of mAb therapy is being investigated.
Fritzj, as I am an epidemiologist -you have ventured into my favorite topic. The 1 in 2 lifetime risk statistic also comes from the SEER website. Incidence rates and lifetime risk are very different because lifetime risk is cumulative over time for an individual, whereas incidence is based on annual population risk.
As far as your question about solid tumors, I don't believe that this has been aggressively attempted, but Davis et al. reports that since large organ transplants can be rejected, some researhers feel that immunotherapy for solid tumors is possible.
In response to jennal7630-
Ah...that's what I wondering. So each adult has a 0.5% annual chance of being diagnosed with "cancer", and the 50% stat is cumulative . I'm no statistician (biochemist), but I'll bet "incidence risk" and "lifetime risk" get frequently mis-quoted or mis-reported by many...what is point of even reporting indcidence then? Who cares if I get cancer this year, versus next year? Thanks for the clarification!
That is so amazing in how many people will be diagnosed with cancer in their lives. I am glad that they are working on new ways to treat cancer patients because I know from relatives that the treatments like chemo can be more painful than the diease itself. Also that was a very interesting idea about the solid tumors. I love hearing new and interesting ideas about treatments for cancer because we certainly need them!
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