The immune system is elegantly designed to help our bodies fight against pathological foreign agents; without it, we would all die of the most minute of infections. Although we do know a lot about how our immune system works, we still do not know enough to create immunotherapies that should in theory eliminate the diseases that they are targeting.
Gastrointestinal stromal tumors (GISTs) are rare cancers that can develop along any part of the gastrointestinal tract. Scientists have observed that mutations in the KIT genes are responsible for causing the uncontrolled proliferation of cancer cells. The first-line immunotherapy for GIST, imatinib, often demonstrates a deep and sustained response, showing the importance of immunotherapy in treating GISTs.
However, other immunotherapies have not been performing as impressively. The challenge for scientists today is to develop new therapies targeting molecular sites that can provide consistent clinical benefits in GIST patients. To accomplish this, scientists need to go back to the drawing board and re-examine the relationship between GIST and the immune system.
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Read more about GIST epidemiology
A team of researchers conducted a literature review investigating the GIST microenvironment as well as current approaches to immunotherapy. Their detailed review was recently published in Frontiers in Immunology. We will take a closer look at some of their findings in this article.
How Imatinib Works
Imatinib is currently the first choice of immunotherapy medications for GIST; it is therefore incredibly important for us to know how it works. Imatinib is a tyrosine kinase inhibitor (TKI) and works by targeting c-kit and PDGFRα. By inhibiting c-kit, imatinib increases the Th1 response, which has the effect of increasing the secretion of IFNγ. This is significant because an increase in the secretion of IFNγ is a major prognostic indicator: studies have shown that if an increase in IFNγ secretion is observed after 2 months of treatment with imatinib, patients have an 85% progression-free survival (PFS) rate, compared to 50% in nonresponders.
Read more about GIST prognosis
In addition, imatinib works by increasing the influx of CD8+ T cells into the GIST, thus amplifying the CD8+ immune response. It does so by inhibiting the tumor overexpression of indoleamine 2,3-dioxygenase (IDO). The resulting effect is the depletion of intratumoral regulatory T cells and an increase in the CD8/Treg ratio. Scientists have confirmed this by observing an increase in CD8+ T cells and fewer regulatory T cells in imatinib-sensitive GISTs.
It has also been suggested that imatinib works by decreasing the expression of programmed death-ligand 1(PD-L1) on tumor cells, which helps the tumor evade immunity. In addition, imatinib inhibits vascular endothelial growth factor (VEGF) transcription in chronic myeloid leukemia. VEGF has been observed to induce an immunosuppressive microenvironment, so its inhibition strengthens the body’s immune response against the disease.
Combination Therapies
Another exciting area of GIST immunotherapy research is the proposal to combine various immunotherapeutic drugs in a bid to strengthen the immune response against cancerous growth. In theory, this sounds like a feasible idea, but real-world results sing a different tune.
For example, immunotherapies combining anti-PD-(L)1 antibodies with anti-CTLA-4 antibodies did not show any improved efficacy against GIST. However, there have been observations of sustained stable disease in some patients, giving hope that the concept of combining immunotherapies may yet yield results if research continues. There is a strong argument to evaluate the efficacy of combining anti-PD-(L)1 antibodies with imatinib. PD-L1 is associated with immune escape; it would be interesting to see how well imatinib performs before immunological escape occurs in earnest in GIST.
Another area in which the combination of immunotherapies can potentially result in an enhanced immune response is in the combination of IDO inhibitors with imatinib. Clinical trials involving IDO inhibitors have been disappointing to date, but IDO plays too important a role for us to give up just yet; IDO-mediated immune escape is one of the key features of how GIST is able to evade treatment. The authors of the review wrote, “We believe that the most promising strategy would be to study IDO inhibitors in combination with imatinib, following progression during imatinib monotherapy.”
The Future of GIST Immunotherapies
There is still a lot of space for exploring the role of immunotherapies in treating GISTs. Beyond imatinib standing as a first-line drug, there are a host of other drugs that are listed under second-line immunotherapies, including sunitinib, regorafenib, ripretinib, etc. We need to have a better grasp of why some immunotherapies function better than others in order to select the best medication for our patients.
In addition, the novel idea of combining immunotherapies has been largely untested. The challenge is to achieve the right combination of immunotherapy drugs to achieve maximum clinical benefit to the patient. This will undoubtedly require a lot of trial and error, but any progress, however small, is worth the fight.
The authors of this review concluded, “We believe three approaches must be highlighted: a better selection of patients included in clinical trials (presence of TLS, PD-L1 expression, PDGFRα-D842V mutation), the use of innovative immunotherapeutic drugs (especially IDO inhibitors), and most importantly the combination of c-kit inhibition with immune checkpoint inhibitors.” That’s plenty of angles to cover. With perseverance and a bit of luck, we just might make some progress in the years ahead.
References
Roulleaux Dugage M, Jones RL, Trent J, Champiat S, Dumont S. Beyond the driver mutation: immunotherapies in gastrointestinal stromal tumors. Front Immunol. Published online August 20, 2021. doi:10.3389/fimmu.2021.715727
Long GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20(8):1083-1097. doi:10.1016/S1470-2045(19)30274-8
