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A new type of cancer “vaccine” eliminates tumors in mice


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XRAYS:  Making Sense of Cancer Headlines

Immunotherapy is treatment that uses the immune system to fight cancer. Still in its infancy, it is a promising therapy that is changing how certain cancers are treated. A new study reports that tumors in lab mice were eliminated when they were injected with two immune system-enhancing agents. This new approach is called in situ (at the original site) vaccination because the injections are given directly into the tumors. It worked on several different types of mouse tumors, including lymphomas and breast tumors. This approach may be safer than conventional immunotherapy because it uses very low doses of the agents and it does not require tumors to have particular markers. (02/23/18)


STUDY AT A GLANCE

This study is about: 

Studying the effectiveness of treating cancer by injecting immunotherapy agents directly into tumors.

Why is this study important?

For decades, researchers have attempted to harness the body’s natural immune system to eliminate cancer. In this study, researchers showed that injecting very small amounts of two immunotherapy substances into the tumors of lab mice triggered an immune system response that eliminated the targeted tumor and other cancers as well. Moreover, the treatment was quicker and less costly than other currently used types of immunotherapies, because there was no need to discover specific targets or customize treatment against them. And since the drug was only injected into the tumor rather than being given systemically (intravenously or orally), the mice experienced less side effects.

Study findings: 

Directly applying two immune agents to tumors is a new approach that worked well in laboratory mice.

  • In mice with transplanted lymphoma tumors at two separate sites, injecting one tumor site with the two agents eliminated both the treated and untreated tumors.
    • 87 of 90 mice were cured of lymphoma
    • Although the cancer recurred in three of the mice, their tumors regressed again after a second treatment.
  • Mice that were genetically engineered to develop breast cancers in all 10 of their mammary pads also responded to the treatment:
  • Treating the first mammary tumor to develop often prevented the occurrence of future tumors and significantly increased the rodents’ life spans.

To determine whether the immune cell response was specific to different cancers, researchers transplanted two types of tumors into the mice: lymphoma cancer cells in two locations and colon cancer cells in a third location.

  • When one lymphoma site was treated, both lymphoma tumors regressed, but the colon cancer cells remained unaffected. 
    • These results suggest a very targeted approach: only tumors with the targeted protein—in this case lymphoma—at the treated site were affected. Treating the lymphoma did not affect the colon cancer.

What does this mean for me?

While this study had excellent results—all of the subjects had substantial responses and lived longer—it is important to remember that this research was done in mice, and lab studies in animals don't always translate to the same results in people. However, both of the agents used in this study are also being tested in humans. One of the agents is already approved for use in humans and is currently being tested in patients as a single agent and in combination with other therapies. The other agent is being studied in early clinical trials. In January, the researchers of this study began a small trial in 15 patients with low-grade lymphoma

If successful, researchers believe this type of immunotherapy treatment could be useful for many tumor types. In the future, patients may receive immunotherapy injections prior to surgical removal of their cancer as a way to prevent recurrence or the development of future tumors that develop from genetic mutations like BRCA1/2.

Questions to ask your health care provider:

  • Is immunotherapy an option for me at this time?
  • Are there any harmful side effects from vaccines, or from immunotherapy in general?
  • Do I qualify for any immunotherapy clinical trials?

IN-DEPTH REVIEW OF RESEARCH

Study background:

Cancer immunotherapy is a treatment approach that uses the immune system to fight cancer. Some immunotherapies increase immune system activity throughout a patient’s body, while others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others involve removal of a patient’s immune cells, genetically engineering them to attack tumor cells and then reintroducing them back into the body. Many of these immunotherapy approaches have been successful, but they also have significant downsides, from debilitating side effects to high cost and long preparation or treatment times.

Researchers of this study wanted to know:

If a mouse immune system could be stimulated to attack cancer cells by injecting a “vaccine” directly into a tumor.

Ronald Levy, MD, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine at Stanford University is the senior author of the study “Eradication of spontaneous malignancy by local immunotherapy,” which was published in the January 31, 2018 issue of Science Translational Medicine

Levy and his team call this new treatment “in situ vaccination” because injecting minute amounts of two immunotherapy agents directly into a tumor triggers an enhanced T cell (a type of immune cell) response. One of the agents used is called a “CpG oligonucleotide,” a short DNA molecule that increases the expression of the OX40 receptor on the surface of nearby T cells. The other agent is an antibody that binds to OX40 receptors and activates T cells to attack tumor cells. The body “prescreens” these activated T cells to recognize only the unique cancer-specific proteins in the tumor. Some of these tumor-specific T cells move beyond the original tumor to find and destroy other identical tumors in the body.

Population(s) looked at in the study:

  • Mice that were implanted with identical lymphoma tumors in two sites.
  • Mice that were genetically engineered to develop breast cancers in all 10 of their mammary fat pads.
  • Mice that were implanted with identical lymphoma tumors in two sites and a colon cancer in a third location.

Study findings:  

After in situ vaccination (injection of CpG and OX40) into one of two lymphoma tumors in 90 mice:

  • 87 mice (97%) were cured of lymphoma.
  • Although the cancer recurred in three of the mice, the tumors regressed again after a second treatment.

Other mice used in this study were genetically engineered to develop estrogen receptor-negative and progesterone receptor-negative tumors in all 10 of their mammary fat pads.

  • In situ vaccination (injection of CpG and OX40) into the first developing mammary tumor:
    • Prevented tumors from developing in other fat pads.
    • Significantly increased the animal’s life span.
    • In some cases, a second tumor was present at the beginning of the vaccination and treatment of a single tumor led to significant reduction in growth of the contralateral tumor.

Finally, the researchers explored specifically how this immune cell response affected different cancers. In mice with implanted lymphoma tumors at two different sites and one colon cancer tumor: 

  • After in situ vaccination (injection of CpG and OX40) into one of the lymphoma tumors:
    • Both the injected and the non-injected lymphoma tumors regressed
    • the colon tumor continued to grow.

In a related experiment, mice that were implanted with two colon cancers and one lymphoma tumor were given an in situ vaccination (injection of CpG and OX40) into one colon cancer tumor:

  • Both the injected and non-injected colon cancer tumors regressed
  • the lymphoma tumor continued to grow.

Limitations:

This study’s results are excellent and exciting: all of the mice that were treated had substantial tumor responses and lived longer.  However, it is important to remember that many cancer therapies that work well in rodents don’t translate to humans. It should also be noted that this approach will only work in tumors that have been infiltrated by the immune system.

A new, small trial of situ vaccination with CpG and OX40 for low-grade lymphoma will soon begin enrolling patients; it will be a starting point to understand whether this approach can be as successful in people as it was in these study mice. Even if the human trial is successful, it will still be years before this type of tumor “vaccination” can be broadly offered to patients.

Conclusions:

Dr. Levy states, “Our [new] approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”  However, he also cautions that if this approach proves successful in humans, it would likely be only one of a number of tools used to fight the cancer.  While exciting, a lot of unknowns about this treatment remain: Will it work on everyone? How many cancers might be impacted? Does it have the potential to overstimulate the immune system?  Further research will be needed to answer these and other important questions.

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Posted 2/23/18

References

Sagiv-Barfi I, Czerwinski DK, Levy S1, Alam IS, Mayer AT, Gambhir SS, Levy R. "Eradication of spontaneous malignancy by local immunotherapy." Sci Transl Med. 2018.  10(426).

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