What Cancer Therapy Is Good To Evaluate As A Second Opinion?

//What Cancer Therapy Is Good To Evaluate As A Second Opinion?

Are you looking for a second or third opinion of the cancer therapy for your beloved family member or yourself? If so, knowing the history of immunotherapy can be quite beneficial. That’s because immunotherapy has now been fully accepted by the medical profession as a viable treatment of cancer. Yet many doctors are unable to use this type of cancer therapy due to lack of training. It’s not part of the normal curriculum at medical school.

The First Medical Innovation That Led to Immunotherapy

Immunotherapy as a cancer therapy didn’t spontaneously evolve without any previous medical milestones. Actually, what happened first was that the development of vaccination procedures in the 18th and 19th centuries showed medical doctors proof that only 1-2% of smallpox victims would die from the horrendous disease. Those not vaccinated were shoveled into graves at a rate of 36% of those who had contracted the disease. This early vaccine demonstrated that immunity to smallpox was possible and plausible.

Other vaccinations were created after a revelation in medical ideology occurred, such as when Antonio Bassi proposed the idea that microbes caused disease in 1844. Some of those diseases included rabies, cholera, typhoid, diphtheria, pertussis, TB, and tetanus. After 1930, vaccines for different viruses such as yellow fever, flu, polio, measles, mumps and rubella were developed, and are still used today.

The field continued to develop, and through the 1980s, molecular biology, medicinal chemistry and immunological advancements were incorporated, releasing vaccines for prevention of meningitis and pneumonia due to the Pneumococcus bacteria as well as hepatitis B. This led to the idea that perhaps the immune system could be instrumental in fighting cancer in the 1980s.

It wasn’t the first time the idea about the tie between the immune system and cancer treatment had emerged. In the late 1800s, William B. Coley, a surgeon, was taken aback when his patient died of a sarcoma (solid tumor) that had metastasized. At that time, cancer centers and treatment centers for cancer were only thinking of poisoning the tumor or cutting it out. Cancer diagnosis didn’t include testing the immune system.

Coley bravely thought outside the box that perhaps immunotherapy would work and then vetted his idea with 47 case studies in the medical literature that gave him a clue that infection at the same time as cancer in these patients was responsible for the total turnaround of incurable cancers. He found that a Streptococcus infection in the deep layer of the skin called the dermis caused a remission of sarcomas.

When he vaccinated his sarcoma patients with heat-killed S. pyogenes and S. marcecsens bacteria (a Gram-positive and Gram-negative bacteria, respectively), he found that the immune system was stimulated. Other doctors’ cancer treatments couldn’t come close to his excellent long-term success cure rates. Interestingly, Dr. Coley’s immunotherapy-based cancer treatment remained unrivaled by medical science for 81 years after his death in 1936.

The only problem with Coley’s cancer treatment in his time was that he couldn’t explain it medically. Science hadn’t caught up to provide the biological basis of it. However, his discovery led researchers to uncover the following:

  • signaling factors that occur in the body that modulate immune function
  • receptors inside the body that detect infectious organisms through pattern recognition
  • checkpoint inhibitors inside the body that are used to affect cancer treatments

Cancer Therapy Now May Include Other Ways to Stimulate the Immune System

Doctors at cancer centers have found that cells that suppress the immune system surround certain types of cancers as if they were guarding the tumor. When this happens, the patient with cancer can’t really make any headway against the cancer. The purpose of the immune system is to fight any foreign invaders, cancer cells included.

When certain types of cancer treatments are used as therapy, it’s possible to activate the immune system. As examples, cryoablation, radiofrequency ablation (RFA), microwave ablation (MWA) and focused ultrasound (FUS) are the treatments for cancer that do exactly that. What these methods do is use cold, heat, ultrasound or radio waves to make the tumor implode/explode. The tumor is literally destroyed.

How These Cancer Treatments Really Work

But there’s something else that is happening with these cancer treatments. Ablation ends up making the protein antigens from the tumors available for the creation of a “cancer vaccine” right there in the area where the tumor was. The immune system is stimulated, and now the body can cause an all-out immune system response that has effects throughout the entire body.

If there were any additional tumors that started growing in other places of the body, the immune system will attack them. The process whereby a cancer treatment applied in one area of the body ends up causing the breakdown of other tumors in the body is called the abscopal effect. The effect has to be combined with other immunotherapies to be more effective and produce long-term anti-tumor effects by stimulating immunity.

Difference Between Ablation and Surgery

Ablation therapies have a goal similar to that of surgical resection where the tumor is removed. However, there is a difference between the two. Surgery removes the tumor as best as it can; ablation leaves the tumor material at the site.

Of course, most of the tumor has been destroyed, but fragments still remain. It’s the fragments that cause the triggering of the immune system and the subsequent destruction of any metastases. Surgery doesn’t do this.

What is Cryoablation and What are DAMPs?

Cryoablation creates a freeze-thaw cycle in the tumor via argon gas. It causes death of the cells, but the cells release antigens, damaged heat shock proteins, and damaged DNA. The damaged cells are also called damage associated molecular patterns or DAMPs for short.

The dendritic cells that “eat up” these damaged cells activate a part of the immune system that creates the expression of CD80/86 molecules, which in turn stimulates T cells in the body and ends up causing the immune system response in the entire body.

Some researchers call the process of cryotherapy loading up the dendritic cells with the antigens an “in vivo dendritic cell vaccine”. The words “in vivo” mean “inside the body”. Thus, the meaning of the whole term is that the body is creating its own vaccine, orchestrated by the dendritic cells. This whole process is quite intricate and amazing!

Researchers have also noted that the activation of the immune system by cryoablation is the most powerful type of ablation cancer treatment. Why? It’s because this cancer treatment actually creates the highest levels of immune system fighter cells, such as the interleukin-1 (IL-1), IL-6, NF-xB, and tumor necrosis factor-alpha.

At the site of the cryoablation therapy, the cold temperature causes the death of the tumor cells, too. These dead cells release protein antigens that the dendritic cells pick up.

The only difference is that the DAMPs won’t be released in the process. Without the DAMPs the immune system is not activated and may be suppressed. This is why it is said that cryoablation alone can cause stimulation or suppression of the immune system. It’s also the reason why cryoablation should be combined with immunotherapy. With the addition of immunotherapy techniques, they can avoid the suppression of the immune system.

How Radiofrequency Ablation Works

Radiofrequency ablation causes cell death by the heat produced in the process plus the death of the cells. When the cells die, they release the antigens and DAMPs. The dendritic cells pick up the damaged cell parts and cause the stimulation of the immune system throughout the whole body.

This cancer treatment causes a persistent increase in the antibodies against the tumor cells; however it also causes lower levels of oxygen that ends up making cancer cells that escaped from the area to grow in new locations. For this reason, doctors and scientists are combining immunotherapies to boost the immune system when radiofrequency ablation is used.

How Microwave Ablation and Focused Ultrasound Work

Microwave ablation uses an electromagnetic field that oscillates to release heat that damages cells – cancerous and normal cells. The immune system response is a lot less than the previously mentioned treatments for cancer. Thus, few studies have attempted to look at what results would be like when microwave ablation is combined with immunotherapies.

Focused ultrasound, when it’s the high intensity version, causes death of the cells at a focal point. The cells die outright, and cells nearby as well my die. Antigens of the tumor cells and heat shock proteins as well as DAMPs will then stimulate the body’s immune system. This cancer treatment offers minimal immune system stimulation compared to cryoablation and radiofrequency ablation.

Different Types of Immunotherapies

Pharmaceutical drugs have been created for use as immunotherapy during cancer treatment. There are two categories of these agents: 1) those that activate the body’s innate immune system processes, and 2) those that activate the body’s adaptive immune system processes.

The innate part of the immune system responds rapidly because it uses pattern recognition to identify the cells to attack. The body’s adaptive immune system refers to the long-term memory of the immune system cells to attack invaders that have already been dealt with in the past.

For example, if you ever had a Staph infection, your body would develop antibodies against the type of Staph you, and store this knowledge in its data banks. When faced with the Staph bacteria again, your body’s cells would recognize it and then fight against it heartily.

Checkpoint inhibitors target the body’s adaptive immune response. There are regulatory checkpoints that prevent the activation of the immune system to occur inappropriately. When doctors inhibit these checkpoints, the immune system revs up its boosting powers. Checkpoint inhibitors have been approved for the treatment of the following:

  • melanoma
  • bladder cancer
  • Hodgkin’s lymphoma
  • Merkel cell carcinoma
  • solid tumors
  • renal cell carcinoma

One Stanford study showed that when a checkpoint inhibitor called anti-CTLA4 antibody was injected, there was toxicity to the immune system, but once it was used locally in low doses, the results were much better. It triggered a tumor attack throughout the entire body without toxicity to other organs.

In 2013, Fransen et al published medical research in the Clinical Cancer Research journal proving that CTLA-4 inhibitor antibody, when used in a slow release formula, was a very effective way to activate the T cell response that causes anti-tumor effects. A very small dose was used – only one-eighth of the regular dose used in the past – which ended up giving excellent results. The dose decreased the chance of any side effects.

Summary

From this discussion of how immunotherapy started to how different cancer treatments affect the immune system and finally including how specific types of immunotherapies work, you can see why Williams Cancer Institute is excited about the possibilities. They’ve been used ablation combined with immunotherapy for several years now, and getting excellent results. It’s because the cancer treatments used make sense.

If you or a loved one are looking for a second opinion, give them a call at Williams Cancer Institute.

Resources

Decker, William K.; da Silva, Rodrigo F.; Sanabria, Mayra H.; Angelo, Laura S.; Guimaraes, Fernando; Burt, Bryan M., and Kheradman, Farrah. Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models. Front Immunol 2017;8:829. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539135/

Mehta A, Oklu R, Sheth RA. Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response? Gastroenterol Res Pract. 2016;2016:9251375.

Chu KF, Dupuy DE. Thermal Ablation of Tumours: Biological Mechanisms and Advances in Therapy. Nat Rev Cancer. 2014;14(3):199–208.

van den Bijgaart RJE, et al. Thermal and Mechanical High-Intensity Focused Ultrasound: Perspectives on Tumor Ablation, Immune Effects and Combination Strategies. Cancer Immunol Immunother. 2017;66(2):247–58.

Bandyopadhyay S, et al. Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape. J Immunol. 2016;196(4):1964–76.

Ng J, Dai T. Radiation Therapy and the Abscopal Effect: a Concept Comes of Age. Annals of Translational Medicine. 2016;4(6):118.

Sabel MS, et al. Rate of Freeze Alters the Immunologic Response After Cryoablation of Breast Cancer. Ann Surg Oncol. 2010;17(4):1187–93.

Marabelle, Aurelien; Kohrt, Holbrook; and Levy, Ronald. Intratumoral anti-CTLA-4 Therapy: Enhancing Efficacy While Avoiding Toxicity. Clin Cancer Res 2013 October 1;19(19). http://28risi1k3a541b3d3m2ufwoh-wpengine.netdna-ssl.com/wp-content/uploads/2017/05/intratumoralCTLA4.pdf

Fransen, Marieke F.; van der Sluis, Tetie C.; Ossendorp, Ferry; Arens, Ramon; and Melief, Cornelius. Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell-Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects.

By | 2018-07-24T17:31:35+00:00 June 18th, 2018|Uncategorized|0 Comments

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