Optimal outcomes, and perhaps even a cure, could be achieved with the combination of targeted therapies and immune checkpoint inhibitors.
Padmanee Sharma, MD, PhD
James Allison, PhD
Optimal outcomes, and perhaps even a cure, could be achieved with the combination of targeted therapies and immune checkpoint inhibitors, postulated Padmanee Sharma, MD, PhD, and James Allison, PhD, in a paper published inCell.
Immunotherapies, specifically the immune checkpoint inhibitors, can successfully unleash an anti-tumor T cell response, resulting in durable long-lasting responses in select patients. However, these exceptional responses are generally only seen in a small portion of patients, the researchers wrote.
On the opposite side of the spectrum, molecularly targeted therapies have demonstrated clinical responses in the majority of patients who harbor a specific molecular driver, although these responses are short-lived and do not result in durable responses.
The rationale behind a combination of the two approaches is based on the types of responses seen with each type of therapy. Researchers hope that a combination approach could combine the best qualities of each therapy.
In general, upon treatment with a targeted therapy antigens are released during the apoptosis phase. These antigens are taken up by antigen-presenting cells and shown to T cells, which results in the production of activated T cells.
These newly formed T cells will initially breakdown the tumor; however, resistance forms through the acquisition of inhibitory molecules, such as PD-1 and CTLA-4, to shield the tumor from the immune system. Using immune checkpoint inhibitors could stop this upregulation, warranting a combination approach. This approach could be combined to other antigens or resistance mechanisms, the researchers theorized.
“T cells are specific; they recognize and attack tumor-specific antigens down to the peptide level. They remember those target antigens forever, so they can thwart recurrence," said Allison, Professor, Department of Immunology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. “T cell response is adaptable, generating custom T cells to match multiple targets found in the genomic diversity of the tumor or generated by new mutations.”
If resistance could be prevented, a durable response rate resembling that seen with immunotherapy could be duplicated with response levels expected with targeted therapies. If this approach were successful, Kaplan Meier curves for overall survival with a combination approach would resemble traditional response curves seen with targeted therapy.
Previous experiences with the combination of the two approaches have shown mixed results. An early phase study looking at BRAF inhibition plus CTLA-4 inhibition demonstrated unfortunately high levels of liver toxicity. However, more recently, a study looking at VEGF inhibition plus immune checkpoint inhibition showed promising results in renal cell carcinoma.
“This highlights that differences in drugs, doses and dosing schedule need to be evaluated as we develop combination therapies,” suggested Sharma, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
More research is needed to perfect this approach, which will require further funding. The authors noted that increased funding for combination therapies could result in new and safe treatments with curative potential across many types of cancer.
“To support this goal and accelerate these efforts, changes in directions of research support and funding may be required,” the authors wrote. “At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer."
This research project would call for collaboration between molecular medicine specialists and immunologists. The separation between these types of researchers calls for further research and initiatives, the authors suggested.
“Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps,” Sharma said.