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Blog #31: Cancer: Current treatment considerations (Part 1: Attacking from the outside and from the inside)
Combination strategies using immunotherapies and genetic procedures in conjunction with chemotherapies, radiation therapies, and surgery are being viewed as the hope for future successes in cancer treatments.
Chemotherapy and radiation therapy differ from immunotherapies and genetic engineering therapies in that immunotherapies use the body’s own cells and chemistry to treat itself. Conversely, chemotherapies utilize toxic biochemical agents to target and destroy tumor and cancer cells throughout the body. The problem with chemotherapy (and radiation therapy) is their indiscriminate, adverse effects on the body. Various forms of chemotherapeutic agents disrupt the stages of irregular and rapid cancer cell development. Unfortunately, they are not specific to the cancer cells alone and tend to disrupt normal cell as well, particularly the more susceptible cells of the gastrointestinal tract and hair follicles, thus causing nausea and hair loss in cancer patients. Chemotherapy is often used in conjunction with or after surgery and/or radiation therapy. These combination therapies help other treatments work better and kill cancer cells that have returned or spread to other parts of the body.
Radiation therapy targets and attempts to destroy tumors and cancer cells in specific areas of the body by using beams of intense energy to kill the cancer cells. X-rays, proton beams, and other types of energy are now being used with considerable success. The radiation is delivered by an external beam or sometimes by an internal source (usually solid radioactive media) placed near the tumor. Radioactive implants are also used directly into the tissue, most often to treat cancers of the head and neck,
breast, cervix, prostate, and eye.
Systemic radiation therapy called radioactive iodine, or I-131 is most often used to treat certain types of thyroid cancer. Another type of systemic radiation therapy is used to treat some patients who have advanced prostate cancer and other rare forms of cancer that effect the pancreas and the brain. Whatever the delivery mode, at high doses, radiation kills cancer cells or damages their DNA and causes the cancer cells to stop dividing or die. This process could take days or weeks before DNA is damaged sufficiently to destroy the cancer cells. Subsequently, the cancer cells keep dying for weeks or months after radiation therapy ends.
Target therapies for cancer are similar to the immunotherapies that use biologic agents for autoimmune diseases. The agents used target therapies differ from chemotherapeutic drugs in that they interfere with specific molecules (“targets”) that are involved in the growth, and the spread of cancer. Targeted cancer therapies are sometimes called “molecularly targeted therapies” and “precision medicines” because they are similar to genetic therapies. As such, they are considered cornerstones in the “precision medicine” concept. Some of the FDA approved target therapies include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis, and checkpoint inhibitors.
But currently, notwithstanding the effective use of combined cancer-fighting technologies, immunotherapies are becoming increasingly favored as first-line treatment choices. The main reasons appear to be better results in arresting and even reversing tumor growth and metastasis as well as reducing negative treatment effects.
Blog #32: Cancer: Current treatment considerations (Part 2: Using our immune system to fight the fight)
In a discussion on immunotherapies in the treatment of cancers, the most appropriate place to begin is with the monoclonal antibodies. These are a type of molecularly targeted cancer therapy we spoke of at the end of our last blog. They are designed to interact with specific targets and as such are the foundation of precision medicine. They target proteins that control how cancer cells grow, divide, and spread. As researchers learn more about the DNA changes and proteins that drive cancer, they are better able to design promising treatments that target these proteins.
Most targeted therapies are either molecules small enough to enter cells easily (called “small-molecule drugs”) so they are used for targets that are inside cells, or they are monoclonal antibodies. Some monoclonal antibodies (Blog #21) are also immunotherapeutic because they help turn the immune system against the cancer. An example would be monoclonal antibodies that mark cancer cells so that the immune system will better recognize and destroy them. One type of monoclonal antibody binds to a protein called on the B cells along with some types of cancer cells, causing the immune system to kill them. Other monoclonal antibodies called immune checkpoint inhibitors (see Blog #21) bring T cells close to cancer cells, helping the immune cells to kill the cancer cells. One type of monoclonal binds to a protein found on the surface of leukemia cells and a protein on the surface of T cells. This process helps the T cells get close enough to the leukemia cells to respond to and kill them (Fig. 6.1).
Up to this point, we have described numerous immunotherapeutic approaches developed to redirect and/or increase immune functions against tumor cells. Another way is the transfer of cells, usually immune cells [from self or from another], with the goal of improving immune function for the treatment of malignant cancers. This approach has now been expanded by the use of T lymphocytes “engineered” to express chimeric antigen receptors (CARs) to produce genetically engineered CAR-T as was described back in Blog #25.
As with CAAR-T cell therapy (see Blog #25), CAR-T cell therapy (Figure 6.3) has been used in cancer treatment for more than 25 years, resulting in four generations of improving therapy that has generated effective therapeutic responses for up to 4 years in some studies. A recent report (February 2022) documented 2 patients with chronic lymphocytic leukemia (CLL) treated with CAR-T therapy 10 years ago remaining in remission. This suggests the therapy to be a “cure” (remember how careful we have to be with that word) for CLL. Based upon the high rates of initial cancer remission and durable responses in many patients receiving CAR-T cell therapy, the transfer of cells has expanded with CAR-T cell therapy and is now being applied against numerous other cancer-producing antigens with encouraging clinical response data being reported. Again, as previously described about the combination of stem cells with CRISPR-Cas9, so too can CAR-T cell therapies be expanded in combination with CRISPR-Cas9 and stem cell transplantation.
Blog #33: Cancer: Current treatment considerations (Part 3: When our own immune system clones its way to care)
Way back in Blog #9, we referenced the Idiotype-anti-idiotype Regulatory Circuit (or Loop) and postponed its full discussion because of its complexity and more so, its relevance to cancer therapy. Now we’ll take our best shot at describing this “Idiotype-anti-idiotype Regulatory Circuit (or Loop)” with the goal of “…making it as simple as possible, but not simpler” (Einstein). So, here goes.
This complex theory starts with part of an antibody (an “arm” of the “Y” shape of antibodies) binding with a specific antigen. (easy so far.) Generated B cells begin to produce genetically cloned antibodies with unique profiles of epitopes or idiotypes (surface receptors). These are antigen binding sites for the cloned antibodies. These idiotypes increase their immunogenic stimulation through chemical bioregulators. These cloned antibodies begin producing an abundance of (cloned) B-idiotype cells. These B-idiotype cells generate the set of epitopes (proteins that determine antigenicity) on the
"V” region (of the “Y”) of additional antibody molecules. (The “easy part” didn’t last too long, did it?) This stimulation induces anti-idiotype and anti-anti-idiotype antibodies (called antibody-2, antibody-3, and beyond) ultimately suppress continued immune stimulation by binding with compatible Ts (T suppressor cells). This binding produces a regulatory closed-loop suppressor system (or circuit). It provides a continuing supply of antibodies that can eliminate a persistent antigen, like the carcinogen or carcinogenic stimulus in the case of cancer (Fig. 6.2). These anti-idiotype antibodies have the potential to provide long-lasting immunity, like a vaccine for cancer and for COVID-19. And that’s the big takeaway!
This “Idiotype-anti-idiotype Regulatory Circuit (or Loop),” also referred to as the “idiotype network theory (INT)” was discovered and described by a Danish immunologist, N.K. Jerne, who was awarded the Nobel Prize for medicine in 1984 for his work. But, between you and me, many scientists (myself included) still don’t fully understand what it all means (I told you it was complex!). But its potential benefits in therapies for autoimmune disease (e.g., multiple sclerosis, myasthenia gravis) as well as cancers and COVID-19 vaccine development, to our public health and humanity, definitely earns it a place in this discussion. Imagine, a vaccine for cancer? You’ve gotta wonder what the “anti-vac luddites” will say about that.
By the way, if you have been following the Figures through the many blogs, you may have noticed an evolving diagram starting back in Blog #5 with progressive figures (1.2, 1.4, 1.5, 1.6, 2.1, 2.2, 2.3, 5.1 and finally, 6.2 here) completing the full immune system flow diagram described throughout the text. These diagrams represent the evolution of the human immune response from innate immunity to its completion as response resolution, chronic inflammation or autoimmunity. Quite a biomedical journey, and we're not quite finished.
Blog #34: Cancer: Current treatment considerations (Part 4: Combining our discoveries may be our greatest discovery)
Back in Blog #9, I promised to return to this (yet another) complex topic, but I also promised to be brief. So, once again, let me take a quick shot at making this particular aspect of cancer therapies “as simple as possible, but…" Yeah, yeah, you know.”
Cancer immunotherapy, also known as immuno-oncology, is a form of cancer treatment that uses the power of the immune system to treat and hopefully, eliminate cancer. There are numerous forms of immuno-oncology, many of which we have discussed above including targeted antibodies, cancer vaccines, adoptive cell transfer, checkpoint inhibitors, cytokines, biologics, gene therapies, and treatments given in addition to the initial treatment, e.g., surgery, chemotherapy, radiation, or targeted therapies. Combinations of these types of therapies, particularly with certain monoclonal antibodies effecting targeted immune checkpoints, have shown considerable promise in cancer therapies.
A research scientist with the MD Anderson Institute, Jim Allison, Ph.D., yet another immunology Nobel Laureate (2018), invented immune checkpoint blockade immunotherapy which blocks a protein (CTLA-4) found on a certain T cell (cytotoxic T-lymphocyte) freeing these killer immune cells to attack cancers. Blocking the CTLA-4 also liberates T cells to assume new identities, including one that is vital to an effective response against tumors. CTLA-4, along with a programmed protein (PD-1 – descripted in Blog #21 and 29) have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its fellow protein PD-L1 (on the cancer cell) in combination with another drug targeting CTLA-4 (Nivolumab [Opdivo]) have been approved for treatment of different types of cancers and several others are in advanced stages of development.
The drugs, when administered as monotherapies, showed dramatic increase in their durable response rates and had manageable safety profiles for patients, but more than 50% of patients failed to respond to treatment. A combination of CTLA-4 and PD-1 blockers were evaluated to increase the response rates in patients. In combination they showed significant enhanced efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma, and metastatic colorectal cancer. The success of such “combination strategies” has encouraged multiple clinical studies in other cancer types. The efficacy of combinations has been shown in a number of published studies and more combination therapies are under evaluation in multiple ongoing studies. They will include surgery; chemotherapies; radiation therapies (X-rays and proton beam); “molecular target therapies”; biologic agents; hormones; signal transduction inhibitors; gene expression modulators; apoptosis inducers; angiogenesis inhibitors; “small-molecule drugs”; checkpoint inhibitors; and monoclonal antibodies; as well as genetic engineering (editing and replacement therapies); and stem cell therapy. Clearly, combination therapies guided by artificial intelligence will play a significant role in future treatment of cancers.