March 1, 2018 (Vol. 38, No. 5)
Molecular Imaging Could Help Clinicians Accurately Select Patients for Treatment or Monitoring
The immune system has two fundamental (and contrasting) jobs: spare normal cells (which carry self-antigens) and attack pathogenic cells (which carry nonself-antigens). Somewhere between normal cells and exogenous pathogens are cancer cells.
Although cancer cells are derived from normal tissues, they harbor DNA mutations that often result in tumor-specific molecules that can induce an immune response. Still, cancer cells often evade immune surveillance, as demonstrated by cancers that develop to the point of being clinically recognized, notes Lance Leopold, M.D., the group vice president for immuno-oncology development at Incyte.
Scientists are now developing therapeutics to target the pathways that help cancer cells evade an immune response. From inhibiting key checkpoints that regulate immune activity, to developing new chimeric antigen receptor T cells (CAR-T), to using molecular markers to predict responses to immunotherapies, researchers are working to make cancer treatments as effective as possible. Some of the work was presented at Immuno-Oncology 360°, a conference recently held in New York.
Turning T Cells against Cancer
A key immune checkpoint pathway, PD-L1/PD-1, now validated as a target for several approved therapies, regulates a T-cell surface receptor that inhibits T-cell activation. Targeting this interaction can coax T cells to attack cancer cells. That’s the basis for Merck & Co.’s PD-1 inhibitor Keytruda (pembrolizumab), which was approved in 2014 by the FDA and is now used to treat forms of lung cancer and bladder cancer along with melanoma and classical Hodgkin lymphoma. While this drug has proven useful for treating cancer patients, it is effective in only a subset of patients, leaving researchers looking for other pathways to target in combination with the PD-1 inhibitors.
Indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) is another regulator of immune-cell activity. It was first discovered to have a potent role in immune tolerance between a mother and fetus. This enzyme is commonly expressed and results in the depletion of a key nutrient required for T-cell activation and function, tryptophan, Dr. Leopold says. Inhibiting IDO1 reverses the inhibition of T cells, facilitating immune surveillance and tumor destruction.
The inhibition of IDO1 is the goal of epacadostat, an investigational drug developed by Incyte. The company has been running a Phase III trial to evaluate the efficacy, safety, and tolerability of a combination of epacadostat and pembrolizumab in patients with metastatic melanoma.1
Based on other trial response rates in patients, Dr. Leopold says the company has “hope and optimism” that the combination treatment will produce results superior to those obtained with pembrolizumab alone. Data from the Phase III clinical trial should be available later this year.
A Novel, Nonspecific CAR-T
NKG2D ligands are proteins that are absent from, or present only at low levels on, the surface of normal cells, but they are overexpressed by infected, transformed, senescent, or stressed cells. Researchers at Celyad, building off work by Dartmouth researcher Charles L. Sentman, Ph.D., are testing CAR-T cells with engineered NKG2D receptors to see if the modified cells can recognize and latch on to any of the eight NKG2D ligands expressed by stressed cells.
By fusing an NK cell-surface receptor—the Natural Killer Group 2D protein—to the CD3ζ cytoplasmic domain of the T-cell receptor, the researchers have developed a novel CAR. T cells outfitted with this CAR could attack multiple types of cancer, says David Gilham, Ph.D., the vice president for research and development at Celyad, based in Belgium.
What could be quite advantageous about this approach is that other cell types in the tumor environment will also signal they are stressed, so the therapy could target these cells as well, making it harder for the tumor to survive. The downside, Dr. Gilham notes, is that many healthy cells may have these stress surface ligands expressed as well, so the scientists have to be very careful to ensure those cells aren’t being targeted and killed by the CAR-T cells, too.
In Phase I clinical trials,2,3 the treatment has proven to be safe, suggesting the CAR-T cells are attacking the cancerous cells and not healthy ones. Patients received no pretreatment with chemotherapy drugs before the infusion of the CAR-T cells, which is usually standard protocol.
Dr. Gilham states that research in animal models had suggested that this kind of pretreatment was not necessary, so researchers have been treating cohorts without it. The goal, he continues, is to test the CAR-T cells’ safety first and foremost. And, he adds, the researchers want to ensure any effects of the treatment are due to the CAR-T cells themselves, not something administered at the same time as the CAR-T construct.
Preconditioning treatments may be added in future trials. “We’re very cautious about how to proceed,” Dr. Gilham admits. “But we’re encouraged by what we’ve seen to date.”
CYAD-01 (CAR-T NKG2D) is the lead CAR-T cell approach that is being developed by Celyad. The technology is based on preclinical work carried out by Professor Charles Sentman at Dartmouth College (USA), who demonstrated that T-cells engineered to express the Natural Killer Receptor Group 2D (NKG2D) receptor fused with the CD3? chain of the T-cell receptor complex can drive impressive antitumor activity against established tumors in mouse models.
Determining Whether Patients Will Benefit
Immunotherapy has revolutionized how doctors treat the disease. However, not all patients respond to the new therapies. Each individual’s immune system is wired slightly differently. Consequently, some people are more sensitive to cancer while others are less so. Recognizing these differences in sensitivity, researchers are now looking for biomarkers that can predict which patients will respond to treatment.
The first biomarker assays approved by the FDA targeted PD-L1 expression, but because tumor biology and immunity are complex, a single type of biomarker is not sufficient. That has led investigators to conduct biomarker investigations spanning protein expression, genomics, and transcriptomics. For example, researchers are looking at the correlation between genomic markers and PD-L1 expression.
Maher Albitar, M.D., senior vice president, chief medical officer, and director of research and development at NeoGenomics Laboratories, is leading a study of genes implicated in non-small cell lung cancer (NSCLC) and colorectal cancer. Dr. Albitar’s group is evaluating whether these genes, which include ERBB2, FGFR1, FGFR2, FGFR3, SRC, JAK3, ERBB4, ERBB2, TP53, and SMAD4, correlate with PD-L1 expression.
The investigators found that PD-L1 expression is significantly lower in colorectal cancer compared with NSCLC. They also determined that in NSCLC patients, PD-L1 expression is significantly higher in tumors with mutated TP53. So, there’s a correlation between TP53 mutation in NSCLC and the expression of PD-L1, but not in colorectal cancer, even though the tumor types had similar rates of TP53 mutation.
“This suggests a possible difference in the mechanism of regulating PD-L1 expression between the two tumor types,” the team wrote in a poster4 available on the company’s website. Negative correlations between PD-L1 expression and EGFR in lung cancer and BRAF in melanoma have also been identified, along with positive correlations between PD-L1 expression and Met amplification in lung cancer and between PD-L1 expression and the lack of TP53/Ras mutations in colorectal cancer, Dr. Albitar notes in a related webinar.5
Biomarkers through Imaging
Molecular imaging is a noninvasive way to evaluate tumors and, as a result, could help clinicians accurately select patients for immuno-oncology treatments or monitor their responses. Current imaging technology falls short of this promise, though. It does not allow doctors to evaluate trafficking of activated T cells into tumors or how treatment affects the tumor.
At Imaging Endpoints, Ronald L. Korn, M.D., Ph.D., the company’s founder, chairman, and chief medical officer, has been working with colleagues to integrate positron emission tomography (PET), magnetic resonance imaging (MRI), and other techniques into a system that can quantify how well cancer treatments work. In one study, the team examined whether features of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to the FDA-approved nanoliposomal irinotecan treatment for pancreatic cancer.
In tumors, the uptake of FMX nanoparticles is similar to the uptake of the drug, suggesting that the FMX nanoparticles could offer a way to monitor how well the drug shrinks tumors. In Clinical Cancer Research,6 Dr. Korn and colleagues report, “higher FMX levels were associated with greater reduction in lesion size after nal-IRI treatment,” suggesting that quantitative FMX-MRI “may serve as a predictive biomarker for nanoparticle-based drug delivery.”
PET imaging with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with CT scanning, called 18F-FDG PET/CT, may also be an option. Study results show that such imaging can be useful for tracking tumors in advanced pancreatic cancer patients treated with the chemotherapy drugs nab-paclitaxel plus gemcitabine.
PET/CT imaging successfully tracked changes in tumor metabolic activity at 6 and 12 weeks, the researchers report, noting that PET analysis could be used to determine how effective other investigational agents are in treating advanced pancreatic cancer.7 The team is working on others too, such as the anticancer agent RRx-001 in conjunction with the MRI contrast agent, Gd-LC7-SH.8
“It’s exciting times for the whole field,” Dr. Gilham says.
1. “A Phase III Study of Pembrolizumab + Epacadostat or Placebo in Subjects with Unresectable or Metastatic Melanoma” (Keynote-252 / ECHO-301).
2. “Safety Study of Chimeric Antigen Receptor Modified T-Cells Targeting NKG2D-Ligands“.
3. “A Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Cancer Indications (THINK)“.
4. S. Agersborg et al. “PD-L1 Expression Correlates with TP53 Gene Mutation Status in Lung Cancer but Not in Colorectal Cancer“.
5. M. Albitar, “Comparison of PD-L1 Companion, Complementary and Laboratory Developed Tests with Molecular Profiling” (webinar).
6. R.K. Ramanathan et al., “Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study,” Clin. Cancer Res. 23(14): 3638–3648, (July 15, 2017).
7. R.L. Korn et al. “18F-FDG PET/CT Response in a Phase I/II Trial of Nab-Paclitaxel Plus Gemcitabine for Advanced Pancreatic Cancer,” Cancer Imaging 2017 17: 23.
8. N. Raghunand et al., “Magnetic Resonance Imaging of RRx-001 Pharmacodynamics in Preclinical Tumors,” Oncotarget 8(60): 102511–102520 (June 12, 2017).
