As 2019 progresses, cancer immunotherapy with checkpoint inhibitors will continue its evolution with multiple combination strategies that “will greatly improve responses,” a leading authority in the field predicted.
Two strategies will lead the way: combinations of different types of checkpoint inhibitors and combinations pairing a checkpoint inhibitor with chemotherapy, radiation therapy, and molecularly targeted agents. Combination therapy will build on the transformative foundation that immunotherapy established over the past few years in oncology.
“The field of immunotherapy is exploding,” 2018 Nobel Laureate James P. Allison, PhD said in Cancer Research Catalyst, the official blog of the American Association for Cancer Research (AACR). “For the first time, we have several potentially curative treatments for cancer, with some patients remaining cancer-free a decade or more after treatment.”
Development of checkpoint inhibitor-based combinations has to proceed in an evidence-based manner, added Allison, of the MD Anderson Cancer Center in Houston. That requires careful evaluation of tissue samples from cancer patients to guide drug selection and choose the right drugs, given at the right time, to optimize effectiveness.
“That’s going to be the biggest thing this year,” said Allison.
Allison was one of three cancer scientists who contributed to the blog. AACR president-elect Elaine Mardis, PhD, of Nationwide Children’s Hospital in Columbus, Ohio, and Brian Rivers, PhD, of Morehouse School of Medicine in Atlanta, also offered predictions for precision medicine and for cancer prevention and health disparities, respectively.
Currently, about a third of cancers respond to immune checkpoint inhibitors. Additionally, many patients who initially respond to the agents eventually develop resistance. Another area of emphasis in cancer immunotherapy will focus on strategies to overcome resistance.
Some patients have innate resistance. Combining a checkpoint inhibitor with chemotherapy, radiation therapy, or targeted therapy may overcome that type of resistance, said Allison. In other patients, resistance occurs as a result of acquired defects that lead to loss of response to lytic events or loss of antigen presentation mechanisms. CD4-targeted agents, particularly vaccines, may be effective in that setting.
Refinements in chimeric antigen receptor (CAR) T-cell therapy could lead to more effective treatment in 2019, Allison continued. Many laboratories already are evaluating methods to eliminate genes that inhibit T-cells or to introduce genes that code for specific cytokines or chemokine receptors. More research involving CAR T-cell therapy for solid tumors will come to the forefront, although hematologic malignancies will remain the principal focus.
Advances emerging from large-scale genomics-based studies of tumors will continue to drive developments in precision medicine, said Mardis. Much work remains to unravel the therapeutic implications of certain germline defects, such as the BRCA alterations that led to use of PARP inhibitors and the observation that high microsatellite instability may be a marker for sensitivity to immune checkpoint inhibitors.
“The biggest challenge of next-generation sequencing approaches that identify cancer genomic variants is that much of what we identify cannot be interpreted in terms of impact on function,” said Mardis, citing BRCA variants of uncertain significance (VUS) as an example. “The challenge created by this situation today can potentially be addressed using newer genome editing technologies for high-throughput functional studies that characterize VUS in a medical context.”
The coming year also should yield more systematic studies of liquid biopsy-guided treatment monitoring for drug resistance. Mardis said she also expects 2019 to be a big year for advances in the use of artificial intelligence in “understanding cancer as a system.” Additionally, the recent trend toward more emphasis on “the hardest targets” will continue, as basic and clinical scientists seek more effective treatment for some of the most difficult-to-treat cancers, such as glioblastoma multiforme and pancreatic cancer.
Prevention and Disparities
Rivers predicted an increased emphasis on “implementation science” in cancer prevention and health disparities, which he defined as “the systematic study of methods to promote the adoption and integration of evidence-based practice interventions and policies related to public health, clinical practice, and community settings.”
“Implementation science seeks to understand the behavior of healthcare professionals and other stakeholders as a key variable in the sustainable uptake adoption, and implementation of evidence-based interventions and practices” he said.
Implementation science has great potential in identifying and understanding factors that lead to health disparities, such as gaps in cancer screening in minority and underrepresented populations. Broader and deeper engagement of communities will play a major role in helping to understand and address disparities. Rivers predicted that health disparities will receive more attention at the health policy level in 2019.
Diversification of large databases will increase in the coming year, he added. Investigators already have implemented strategies in recruitment in tumor sample collection in diverse patient populations for cancer genomics studies and eventually molecular profiling.
The AACR has taken a lead role in developing a first-ever cancer disparities progress report, which will provide information and guidance in identifying health disparities and promoting health equity. In late 2018, AACR convened a Cancer Health Disparities think tank to identify next steps in addressing cancer health disparities.
“These initiatives are critical to conducting implementation science research, engaging the community, and ultimately advocating Congress on behavior of cancer research and making progress for cancer patients,” said Rivers.