Tag Archives: immunotherapy

T cells treat squamous cell carcinoma

Immunotherapy and Autoimmune Complications

Immunotherapy has resulted in great achievements in cancer treatments. However, significant adverse side effects have also occurred, often resembling autoimmune diseases.

Harnessing the immune system to treat cancer has long been a dream of researchers and oncologists. After overcoming many obstacles, success seems to have been achieved. An essential feature of the immune system is its ability to distinguish “self,” the body’s own cells and tissues, from “non-self,” originating from outside the body. Cancer cells are derived from normal body cells, so the immune system must somehow recognize them as “non-self” to attack them. Although there is ample evidence that the immune system detects abnormalities in cancer cells in the early stages, the cancer cells have developed many methods to evade the immune system. Immunotherapy, such as the use of checkpoint inhibitors is based on stimulating the immune system to detect and destroy cancer cells. Immunotherapy employs unique molecules present on the surface of cancer cells.

The development of autoimmunity is likely an inherent risk in immunotherapies. Considerable effort is underway to unravel the intricacies of adverse immune reactions to predict when adverse events are likely to occur. New therapies should minimize adverse events while maintaining the effectiveness of checkpoint inhibitors.

Improving immunotherapy strategies can involve identifying differences in antibodies present in autoimmunity resulting from immunotherapy with antibodies present in conventional autoimmunity. also, differences in quantities and types of immune cells can be observed between the two types of autoimmunity. This knowledge can be useful in choosing appropriate immunotherapy regimens.

Individual differences are important, as some individuals may have a genetic predisposition for autoimmunity. The unique composition of the individual’s microbiome may impact the development of autoimmunity by altering the immune composition of the tumor and its microenvironment. This immune composition may alter immune responses to immunotherapy treatments.

REFERENCES
1. Couzin-Frankel, Jennifer. “Researchers tackle vexing side effects of potent cancer drugs.” Science. 2022 Sept. 2; 377 (6610): 1028-1029.
2. Weinmann, Sophia and David Pisetsky. “Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitorts.” Rheumatology. 2019:58: vii59-vii67.
3. Young, Arabella, Zoe Quandt and Jeffrey Bluestone. “The balancing act between cancer immunity and autoimmunity in response to immunotherapy.” Cancer Immunol Res. 2018 Dec; 6 (12): 1445-1452.

How the Microbiome Affects Cancer

The microbiome refers to the collection of all the gene sequences from a community of microbes in the human body. The microbiome has many effects on the human body and may promote cancer progression or aid in controlling cancer. The interactions between the microbiome, diet, host factors, drugs, and cell interactions are complex. Studying the nature of these interactions will require a systems approach.

 

The microbiome may interact with cancer in two ways:  direct interaction (between microbes residing in tissues where cancer emerges), or indirect interaction (between the microbiome and a cancer living in a different tissue). Metastases can carry bacteria from the microbiome of primary tumors to distal tissues.

 

The gut microbiota is closely involved in the development and regulation of the immune system. The immune system is a fine-tuned balance. It must be activated to fight infections, but then deactivated when the threat is overcome to avoid damaging the body’s tissues.  Inflammation is an essential feature of the immune response and can alter the composition of the microbiome so that it can either promote or act against cancer. Some antigens from gut microbes could be similar to cancer antigens resulting in training the immune system to fight cancer.

Patients treated with antibiotics before immunotherapy or chemotherapy fared poorer than patients without antibiotic treatment. The antibiotics may have eliminated beneficial bacteria. Determining the specific species of bacteria responsible has been challenging. In two studies, researchers collected fecal samples from patients ready to receive an immunotherapeutic drug. Both studies identified certain bacterial species present in more significant numbers in patients who responded positively to the drug.

 

There is still much to learn about the microbiome’s effect on cancer progression before treatment strategies can be developed. Some clinical trials are already taking place even though the microbiome’s mode of action on cancer is still largely unknown.  The following are a few proposed  microbiota-oriented interventions that could improve immunotherapy treatment:

  1. Fecal microbiota transplant from patients that have responded to immunotherapy
  2. Prebiotics and diet to promote the growth of beneficial bacteria or starve detrimental bacteria
  3. Antibiotics that destroy detrimental bacteria
  4. Probiotics that contain beneficial bacterial
  5. Drugs based on bacterial metabolic products that improve anti-tumor immunity or lessen the detrimental effects of chemotherapeutics.

Regarding the featured image courtesy of the National Institutes of Health:

The Common Fund’s Human Microbiome Project (HMP) developed research resources to enable the study of the microbial communities that live in and on our bodies and the roles they play in human health and disease. HMP has now transitioned from Common Fund support.

References

  1. Williams, Shawna. “This is your Microbiome on Drugs.” The Scientist, July/August 2019, pp. 38-45. . https://www.the-scientist.com/features/how-the-microbiome-influences-drug-action-66081
  2. Xavier, J. et al. “The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View.” Trends in Cancer, March 2020, vol. 6, no. 3 https://www.cell.com/action/showPdf?pii=S2405-8033%2820%2930017-0

Fessler, Jessica, et al. “Exploring the Emerging Role of the Microbiome in Cancer Immunology.” Journal for Immunotherapy of Cancer.   https://doi.org/10.1186/s40425-019-0574-4

antibody binding

A New Type of Cancer Immunotherapy

A newly emerging type of cancer immunotherapy uses bispecific antibodies. These drugs attach to both immune cells and tumor cells thereby facilitating destruction of the tumor. They are called bispecific as they bind to a unique surface protein, CD3, on an immune T cell and to a antigen marker on a tumor.

Although bispecific antibodies have been studied for decades, the field was slow to develop due to difficulties in designing and producing the drugs. Those problems are now rapidly being overcome. The field continues to evolve with many new designs of bispecific antibodies being prepared. A major advantage of bispecific antibodies is that they can be mass produced in advance.

Bispecific antibody therapy joins other well-established methods of immunotherapy. CAR T cell therapy involves the use of bioengineered drugs. In this approach, T cells are separated from a patient’s blood, and a specialized receptor gene is inserted. The CAR T cells are then multiplied in the laboratory and reinserted into the patient. The CAR T cells have enhanced ability to hone onto cancer cells and destroy them.  CAR T cells, however, must be prepared for each patient, an expensive and slow process.

Another important immunotherapy treatment involves the use of checkpoint inhibitors.  Immune checkpoints are signals used by the immune system to control an immune response. After the immune response has completed its task, checkpoint inhibitor proteins shut down its activity to prevent the immune system from destroying normal tissue. Cancer cells can develop the means to stimulate these proteins to prevent the immune system from attacking the cancer. Checkpoint inhibitor drugs known as monoclonal antibodies can block this action.

All three immunotherapies have their limitations, so many researchers now believe that the most effective therapy could involve using them in combination.

Reference

http://science.sciencemag.org/content/368/6494/930