As we look over the evolution of medicine, we see we have gone from what can be described as crude experimentation in ancient times to more sophisticated ways of managing the signs and symptoms of a disease in the past century. The effort to dig deeper through the layers of a disease to reach its proverbial core has led to the development of therapies based on histological and genetic findings.  

The burst of new immunotherapy drugs over the past few years is consistent with such medical advancements. The promise of immunotherapy is that it fixes the problem at its very root, thus alleviating all signs and symptoms associated with it. If medicine was to plateau at just treating the individual signs and symptoms of a disease, we would be playing an endless game of “whack-a-mole,” which is indeed not effective.

Immunotherapy offers new hope for diseases that currently carry a very poor prognosis. A team of researchers conducted a review of immunotherapy strategies for gastrointestinal stromal tumor (GIST) and published their findings in Cancers.


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Read more about GIST etiology

The researchers did a fantastic job in explaining how immunotherapy works and how it applies to GIST and other diseases. The immune system, as we all know, has 2 main responses: innate (first line of defense) and adaptive (second line of defense). The immune system is also a combination of stimulatory and inhibitory interactions; it is a fine balancing act that can either drive or inhibit disease progression. Many immunotherapeutic drugs rely on the inhibitory mechanisms of the immune system to eradicate tumors or at least slow down disease progression. 

In GIST, tumor-infiltrating cells populate its microenvironment. Researchers have found that this microenvironment is immunosuppressive. Statistics show that almost 70% to 75% of GISTs have KIT mutations; the rest are considered KIT wild-type GISTs. The US Food and Drug Administration (FDA) has approved a few drugs for the treatment of advanced or metastatic GIST. They include imatinib (first-line), sunitinib (second-line), regorafenib (third-line), and ripretinib (fourth-line).

Imatinib, the first-line immunotherapy for GIST, can achieve a progression-free survival of 1.9 years and a median overall survival of 3.9 years. It works by interacting with the immune system at many levels to enhance its antitumor function. In a nutshell, imatinib works by activating CD8+T cells and causing the apoptosis of tumor-infiltrating T-reg cells. Although these results are promising, imatinib is not considered curative because secondary KIT mutations tend to develop, causing resistance to the drug.

There is currently a great amount of research evaluating immunotherapies that target different pathways. This work may produce new classes of immunotherapeutic drugs that can be routinely prescribed in patients with advanced or metastatic GIST in the future. 

Other Immunotherapeutic Options

Having discussed briefly the immune environment in GIST, let us have a look at some of the immunotherapies that are available besides imatinib. 

Cytokine therapy is a form of immunotherapy that increases immune surveillance, which eradicates drug-resistant clones in GIST and improves imatinib performance. Studies have shown that cytokine therapy, such as interferon alfa, can transform immune tolerant cells into antitumor cells, thus targeting GIST more effectively. It also plays a significant role in promoting a Th1 response. 

Read more about GIST prognosis

Immune checkpoint inhibitors are another form of immunotherapy that prevents checkpoint proteins from binding to their associated proteins, which increases the capacity of the immune system to eliminate cancer cells. It works primarily by blocking the PD1-PDL1 pathway, a pathway that typically leads to the evasion of cancer cells. By blocking this pathway, immune checkpoint inhibitors decrease the chances of the tumor bypassing the immune system. 

Anti-KIT antibodies are another class of immunotherapy drugs that have been proven to slow down the in vitro growth of human GIST cells. They do so by downregulating KIT and enhancing the phagocytosis of GIST cells. In addition, they inhibit imatinib resistance, thus boosting its efficacy. Anti-KIT antibodies have also been discovered to increase the clearance of tumor cells by the immune system. 

Another type of immunotherapy medication is bispecific monoclonal antibodies. They work by inhibiting cell proliferation in both tumor cells and normal cells. Scientists also use cellular therapy, another type of immunotherapy, to treat GIST by genetically engineering CD8 T cells with specificity towards GIST cell antigens. This can then contribute towards significant tumor regression.

Immunotherapy Today 

The immunotherapies mentioned in this article are currently not routinely prescribed in GIST care; however, this may change in the future as more research is conducted. This is because research focusing on immunotherapies for GIST is still relatively sparse compared to that on other cancers such as melanoma and non-small cell lung carcinoma. 

However, current clinical trials on GIST immunotherapies “are bringing a new horizon of treatments into view,” according to the authors of the study. Immunotherapy can potentially alter the treatment paradigm of certain diseases such as GIST altogether. However, at present, both physician and patient need to carefully weigh the usefulness of such therapies against their potential toxicity and the financial burden that they can incur. 

References

Arshad J, Costa PA, Barreto-Coelho P, Valdes BN, Trent JC. Immunotherapy strategies for gastrointestinal stromal tumorCancers (Basel). 2021;13(14):3525. doi:10.3390/cancers13143525

Nishida T, Blay JY, Hirota S, Kitagawa Y, Kang YK. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer. 2016;19(1):3-14. doi:10.1007/s10120-015-0526-8