A pre-meeting webinar provided a glimpse of some of the key presentations at the upcoming annual meeting of the American Association for Cancer Research (AACR). Four studies were selected to highlight the themes of immunotherapy, precision medicine, health disparities, and prevention.
Why isn’t CAR-T cell therapy as successful in solid tumors as it is in leukemia and other hematologic malignancies? Why is it more difficult to manufacture CAR-T cells from some pediatric leukemia patients than others?
According to an abstract from a team that pioneered use of CAR-T cells in children with leukemia, poor quality T cells may be the answer to both of these questions.
Research by David M. Barrett, MD, PhD, assistant professor of pediatrics at Children’s Hospital of Philadelphia, and colleagues found that metabolic pathways were associated with the quality of T cells. For example, T cells that use glutamine and fatty acid pathways as fuel sources had excellent CAR-T potential while those that depended on glycolysis, another fuel source, were poorly equipped to undergo the CAR-T cell manufacturing process.
This finding was based on analysis of peripheral blood samples from 157 pediatric patients with hematologic cancers and solid tumors; analysis was performed at diagnosis and after each cycle of chemotherapy.
The CAR-T potential of the T cells was poor in most tumor types prior to chemotherapy, with the exception of acute lymphoblastic leukemia and Wilms tumor (there is not yet a CAR-T product for Wilms tumor), and cumulative chemotherapy was associated with decline in CAR-T potential for all tumor types.
Cells with poor CAR-T potential tended to be those that used glycolysis as their fuel source rather than fatty acids. Certain types of chemotherapy (i.e., cyclophosphamide- and doxorubicin-containing regimens) were especially harmful to CAR-T cell potential.
“We have gotten CAR-T cells to work for leukemia but not yet been very successful in solid tumors. …Our data suggest that poor T-cell starting material may be a key first problem. The T cells from solid tumor patients may need different manufacturing protocols to be successful,” said Dr. Barrett.
Preliminary studies by Dr. Barrett’s group suggest that it is possible to force T cells to use fatty acids for fuel rather than glycolysis, and studies are ongoing to see if this will improve the CAR-T manufacturing process.
Other metabolic pathways may be responsible for poor quality T cells. The research reported today is a first step in elucidating which pathways may be implicated and how to reverse them.
“This study is a great example of the intersection between immunotherapy and precision medicine,” said AACR President Michael Caligiuri, MD, President of City of Hope National Medical Center, Duarte, CA. “Gene expression identifies the energy pathways that T cells use and predict who will do well and who won’t. Then we can try to develop alternative chemotherapies and also try to reverse the metabolic pathways involved.”
HER2 mutations acquired during metastasis appear to confer resistance to hormone therapy in some patients with estrogen receptor (ER)-positive metastatic breast cancer, and the strategy of dual treatment with fulvestrant (a hormone therapy) plus the irreversible HER2 inhibitor neratinib appears to overcome resistance in such cases.
“Resistant ER-positive metastatic breast cancer remains the most common cause of breast cancer death. Although ER-directed therapies are highly effective, most patients invariably develop resistance and stop responding to these drugs,” said Utthara Nayar, PhD, co-lead author this abstract and research fellow at Dana-Farber Cancer Institute Harvard Medical School, Boston.
The researchers conducted whole-exome sequencing of metastatic tumor biopsies from 168 patients with ER-positive metastatic breast cancer that developed resistance to hormone therapies such as tamoxifen, fulvestrant, and palbociclib. HER2 mutations were found in 12 of 168 patients; of these, 8 had mutations previously identified as activating. Further study of 5 available biopsies from these 8 patients revealed that 4 of 5 patients with activating mutations had no evidence of pre-existing HER2 mutations, suggesting that these were acquired under selective pressure of ER-directed therapy.
“It was surprising to discover that HER2 mutations can be acquired in the metastatic setting, suggesting that these tumors evolve, and these mutations seem to be a mechanism of resistance to therapies that target the estrogen receptor….,” said senior author Nikhil Wagle, MD, deputy director of the Center for Precision Medicine at Dana-Farber and assistant professor of medicine at Harvard Medical School.
Laboratory studies showed that HER2-mutation-mediated resistance to hormone therapy could be overcome using the combination of fulvestrant plus neratinib. This strategy was effective in one patient. These early results suggest that dual treatment with these drugs may be a novel strategy for breast cancer patients resistant to ER-directed therapies with acquired HER2 mutations.
Further study is needed to determine the percentage of resistant patients who have acquired or pre-existing HER2 mutations.
Dr. Nayar mentioned that ER mutations, present in 20%-25% of patients with metastatic breast cancer, are known to be responsible for resistance to aromatase inhibitors. Prior to this study, other mechanisms of resistance to ER-directed therapy were unknown in 70%-75% of patients.
“Unlike ER mutations, HER2 mutations conferred resistance to other anti-ER agents,” she said, adding, “This study underlines the importance of profiling resistant metastatic tumors with repeat biopsies. Currently only the initial tumor is profiled in most cases.”
“Using new technologies to examine tumors pre- and post-development of resistance identifies a new mechanism for escaping ER-directed therapy. Excitingly, neratinib can overcome HER2-mediated resistance,” said AACR Program Chair Elaine Mardis, PhD, co-executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH.
“These findings play into the concept of liquid biopsies, because it is difficult to get sufficient metastatic tissue for biopsies. If we know what to look for, we can use liquid biopsies and develop strategies to prolong disease-free survival using next-generation sequencing combined with targeted therapies,” said Dr. Mardis.
Pelvic inflammatory disease (PID) is associated with increased risk of ovarian cancer, and chlamydia is the leading cause of PID in the developed world. Chlamydia infection increases the risk of developing ovarian cancer two-fold, according to data from two independent studies.
In both study populations, women who had antibodies against pGP3, a protein that is an accurate marker of active or prior chlamydia infection, were about twice as likely to be diagnosed with ovarian cancer as controls. No such association with ovarian cancer risk was found with antibodies related to other infections, including human papillomavirus, herpes simplex virus, hepatitis B, and hepatitis C.
“The fact that there were no associations with antibodies against other infectious agents really supports the specificity of the association of chlamydia infection with ovarian cancer,” said lead author Britton Trabert, PhD, MS, Earl Stadtman Investigator in the Division of Cancer Epidemiology and Genetics at NCI, Bethesda, MD.
The two studies included a Polish population-based case-control study of 278 women diagnosed with ovarian cancer between 2000 and 2003 and 556 matched controls, and the NCI-sponsored Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial, a nested case-control prospective trial with blood drawn prior to diagnosis, which included 160 women who developed ovarian cancer during follow-up and 159 matched controls.
The researchers evaluated antibodies to chlamydia and to other sexually-transmitted and non-sexually transmitted infectious diseases. The antibody to chlamydia was the only one found to be significantly associated with ovarian cancer.
Ovarian cancer is typically silent until it is more advanced and, therefore, is associated with a poor prognosis. Identifying a risk factor such as PID or chlamydia infection could enable diagnosis and treatment at earlier and potentially curable stages. The authors plan to confirm their findings in a larger population and determine whether chlamydia infection has a stronger association with specific subtypes of ovarian cancer.
“This study is notable for being an international collaboration for obtaining tissue samples, and it suggests that we can improve detection of ovarian cancer by routine screening for PID and chlamydia,” said Dr. Mardis.
Vulnerable populations are under-represented in clinical trials and biobanking research, hampering research on healthcare disparities. A pilot study of 78 patients and 25 health care providers from Louisiana communities suggests that both patients and providers are open to participation in clinical trials and biobanking but are not well informed about these efforts and are not invited to participate in them. Further, study subjects, including healthcare providers, did not know where to get more information.
According to study participants, the most useful information would be from a “trusted” healthcare provider. Healthcare providers wanted more information about clinical trials and biobanking, and suggested brief, plain handouts with talking points they could share with patients plus a contact person for more information as effective ways to increase participation. Few participants in the trial said that they would look to the internet or social media for information about clinical trials and biobanking.
The study was based on 14 focus groups and 7 individual interviews from January 2017 to May 2017 in urban and rural communities in Louisiana. Among the 78 patient and community participants, 78% were African American, 24% were from rural communities, and 70% reported low income. Among the 25 safety-net health care providers who participated. 10 were physicians, 7 clinical research associates, 5 nurse practitioners, and 3 behavioral health professionals.
“These results highlight a huge communication gap between the cancer research community and potential participants in cancer genomic studies as well as their providers,” said Terry C. Davis, PhD, professor at Louisiana State University Health Sciences Center in Shreveport and at the Feist-Weiller Cancer Center, and director of the Health Literacy Core of the Louisiana Clinical & Translational Science Center. “This issue must be addressed if we are to ensure that new treatments are available and effective for all patients in all segments of the population.”
“There is a communication problem. Less than 10% of the audience at two medical schools where I spoke recently raised their hands to indicate that they were aware of clinical trials and biobanking,” she noted.
Improved relationships with community providers and jointly developed materials on clinical trials and biobanking could help address this gap, Dr. Davis noted. For one thing, language has to be adjusted. In her study, words like “clinical trial,” “biobanking,” and “genomics,” were not
Well understood. “We need a new vocabulary,” she stated.
Dr. Davis said that this was a pilot study in one state, and a larger study including people from even more diverse communities would be needed to strengthen these conclusions.
“This is a simple issue, but the barriers are complex,” said Dr. Caligiuri. “A shocking statistic is that the death rate of all cancers combined is 25% higher for African-Americans than whites. This study points to some of the problems involved in this disparity.”
By John McCleery, Managing Editor, OBR