As much as any other issue, immunotherapy as an option for treatment in cancers is a lightning rod for debate, excitement, controversy, and hope. This is especially true for a spectrum of disorders, particularly soft-tissue sarcomas and gastrointestinal stromal tumors (GISTs). The subject is as volatile as ever, and new results emerging are producing conflicting and confusing information. Let’s look at some of this information as we seek guidance in an area our patients are asking about with more frequency.
The picture in sarcomas is encouraging but largely unresolved, based on data that were presented at the 2016 ASCO scientific sessions in uterine leiomyosarcoma and the use of pembrolizumab (Keytruda®). Immunotherapy, particularly the PD-1 inhibitors, needs much more study before anyone can say it is beginning to fulfill the promise laid out for it in sarcomas.
A major avenue of immunotherapy for sarcoma is adoptive T cell therapy. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Potentially exciting, for sure, but let’s not rush to judgement until we see more results from phase 3 trials currently underway.
By harnessing the class I specificity of the T-cell response, instead of engineering the antigen presentation side of the spectrum, this approach expands a T-cell population that will recognize a particular antigen. The key to the process is the collection and expansion of autologous T-cells with genetic manipulation to alter the T-cell receptor (TCR) phenotype. However, there is a downside to this approach because during the process of expanding the T-cell population immunosuppressive T cells (T regulatory cells) may also be expanded, thus mitigating the efficacy of this modality. To resolve the issue, trials are increasingly incorporating chemotherapy to inhibit immune suppression. Will this strategy prove effective in sarcomas? Stay tuned for all the updates soon to come to a website or medical meeting near you.
Still another intriguing question is whether these adoptive T-cell therapies could be applied more specifically in GIST. In this issue of our journal, Breelyn Wilky, MD, offers a comprehensive and insightful analysis of this and other immune-mediated approaches. It was recently reported, for example, that investigators have developed a KIT-specific chimeric antigen receptor (CAR) for transduction into human T cells. These engineered T cells were effective at suppressing GIST growth in mice models. While these advances are promising, the reported toxicities with adoptive T cell therapy from cross-reaction against normal human tissues are not trivial, and further testing and development will be required before these strategies are ready for clinical testing.
As is noted in the report by Dr Wilky, the excitement surrounding immunotherapy in medical conferences as well as the media is accompanied by a key question: when might GIST patients and their providers want to consider participating in a clinical trial? This decision is particularly difficult given that many trials require patients to stop using tyrosine kinase inhibitors which we generally continue without interruption even in the setting of resistant disease. GIST patients in general do best with uninterrupted suppression of KIT, even when the disease has developed resistance pathways.
We have learned that response to checkpoint inhibitors can take months to manifest, and patients with GIST who abruptly discontinue TKIs can often experience a flare and rapid growth of their disease. Even if patients ultimately respond to immunotherapy, the short-term interval growth can be problematic and lead to medical complications like gastrointestinal obstruction. While laboratory evidence is promising for potential benefit from immunotherapy for GIST, there is still minimal clinical data to guide patients and physicians in whether the science will translate to patient responses in the clinic. Please read the full report by Dr Wilky to get more in-depth information.
To sum up, the excitement generated by the potential of immunotherapy is matched by the challenging questions associated with it. Since it is still a formidable work in progress, one needs to carefully sift through the new data and not rush to judgement on where it can be of benefit to our patients.
Jonathan C. Trent, MD, PhD