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Teaching the Immune System to Attack Cancer with Greater Precision

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Needle in a vial. Cancer cell in the background
Credit: PhotobyTawat/Shutterstock/Tom Deerink, National Institute of General Medical Sciences, NIH

To protect humans from COVID-19, the Pfizer and Moderna mRNA vaccines program human cells to translate the injected synthetic messenger RNA into the coronavirus spike protein, which then primes the immune system to arm itself against future appearances of that protein. It turns out that the immune system can also be trained to spot and attack distinctive proteins on cancer cells, killing them and leaving healthy cells potentially untouched.

While these precision cancer vaccines remain experimental, researchers continue to make basic discoveries that move the field forward. That includes a recent NIH-funded study in mice that helps to refine the selection of protein targets on tumors as a way to boost the immune response [1]. To enable this boost, the researchers first had to discover a possible solution to a longstanding challenge in developing precision cancer vaccines: T cell exhaustion.

The term refers to the immune system’s complement of T cells and their capacity to learn to recognize foreign proteins, also known as neoantigens, and attack them on cancer cells to shrink tumors. But these responding T cells can exhaust themselves attacking tumors, limiting the immune response and making its benefits short-lived.

In this latest study, published in the journal Cell, Tyler Jacks and Megan Burger, Massachusetts Institute of Technology, Cambridge, help to explain this phenomenon of T cell exhaustion. The researchers found in mice with lung tumors that the immune system initially responds as it should. It produces lots of T cells that target many different cancer-specific proteins.

Yet there’s a problem: various subsets of T cells get in each other’s way. They compete until, eventually, one of those subsets becomes the dominant T cell type. Even when those dominant T cells grow exhausted, they still remain in the tumor and keep out other T cells, which might otherwise attack different neoantigens in the cancer.

Building on this basic discovery, the researchers came up with a strategy for developing cancer vaccines that can “awaken” T cells and reinvigorate the body’s natural cancer-fighting abilities. The strategy might seem counterintuitive. The researchers vaccinated mice with neoantigens that provide a weak but encouraging signal to the immune cells responsible for presenting the distinctive cancer protein target, or antigen, to T cells. It’s those T cells that tend to get suppressed in competition with other T cells.

When the researchers vaccinated the mice with one of those neoantigens, the otherwise suppressed T cells grew in numbers and better targeted the tumor. What’s more, the tumors shrank by more than 25 percent on average.

Research on this new strategy remains in its early stages. The researchers hope to learn if this approach to cancer vaccines might work even better when used in combination with immunotherapy drugs, which unleash the immune system against cancer in other ways.

It’s also possible that the recent and revolutionary success of mRNA vaccines for preventing COVID-19 actually could help. An important advantage of mRNA is that it’s easy for researchers to synthesize once they know the specific nucleic acid sequence of a protein target, and they can even combine different mRNA sequences to make a multiplex vaccine that primes the immune system to recognize multiple neoantigens. Now that we’ve seen how well mRNA vaccines work to prompt a desired immune response against COVID-19, this same technology can be used to speed the development and testing of future vaccines, including those designed precisely to fight cancer.

Reference:

[1] Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, Bhutkar A, Canner D, Kienka T, Tavana SZ, Barandiaran AL, Garmilla A, Schenkel JM, Hillman M, de Los Rios Kobara I, Li A, Jaeger AM, Hwang WL, Westcott PMK, Manos MP, Holovatska MM, Hodi FS, Regev A, Santagata S, Jacks T. Cell. 2021 Sep 16;184(19):4996-5014.e26.

Links:

Cancer Treatment Vaccines (National Cancer Institute/NIH)

The Jacks Lab (Massachusetts Institute of Technology, Cambridge)

NIH Support: National Cancer Institute; National Heart, Lung, and Blood Institute

7 Comments

  • Linda D. says:

    This is such exciting news. Can this be used for autoimmune diseases… Like Myasthenia Gravis? (My disease) I would be happy to be in a trial if that were open and in the Nashville area.

    • mark says:

      my wife also suffers with myashenia gravis i have only ten minutes ago after the agm sent an email asking the same question, i asked the question more not for curing myasthenia gravis but for the thymic carcinoma she has had resected , she has now had three operations in the last four years so to hunt and kill any thymic cancer cells would be a godsend

  • david m kerr says:

    When 0.1 ml of vaccine is injected in deltoid muscle, a microhematoma of blood mixed with vaccine forms. The hematoma is probably larger in those with more blood flow to the muscle. Lipid nanoparticle react with red cell and degranulated platelet membranes. The 1% or red cells which are reticulocytes have ribosomes as do platelets (intact or degranulated. Macrophages ingest red cells and platelets in the microhematoma. As professional antigen presenting cells, those macrophages present antigens made from mRNA. Platelet/mRNA fusion antigens may explain thrombotic complications of mRNA vaccines.

    I would like to see a trial of intradermal injection of mRNA vaccines with one minute of firm pressure applied to the site, to reduce the number of platelets and red cells. Vaccine which reacts with red cells is “wasted”

  • Elaine Jesmer says:

    Is this protocol available to blood cancer? Seems the focus is usually on tumors.

  • Larry W. says:

    I’m glad they are doing this for cancer. I wish someone would try and find a cure or something to slow down Lupus and Ms I’m hoping they will soon.

  • Linda D. says:

    Lupus, MS, MG, all of the auto immune diseases could benefit from a trial specific for autoimmune diseases along with a trial for cancer. Both would profit. I would take part if anyone would ask me. There seem to be many of us out here willing to help. Many who seem to be suffering.

  • Fahmida P. says:

    “Cancer Vaccine” it’s a light of hope for those who are suffering. Good luck for a better result.

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