publication date: Apr. 5, 2019
SU2C-supported trials seek to extend CAR T-cell therapy to solid tumors
Stand Up To Cancer is helping scientists make progress in one of the most important areas of cancer research today: expanding the use of autologous CAR T-cell immunotherapy beyond leukemia and other blood cancers to solid tumors, such as osteosarcoma and mesothelioma.
The research could pave the way for a dramatic expansion of a therapy that has revolutionized treatment of blood malignancies but thus far, has had little impact on the solid tumors that make up most cancer cases.
Difficulties in applying the therapy to solid tumors have included the identification of antigens that will serve as targets for the CAR T-cells; getting the cells to the tumors, to stay there to attack the cancerous cells, and dealing with the immunosuppressive environment of the tumor.
Two clinical trials supported by SU2C illustrate the promise of CAR T-cell therapy in solid tumors and were featured at a press conference today at the Annual Meeting 2019 of the American Association of Cancer Research, which is also SU2C’s Scientific Partner. They are:
Prasad Adusumilli, first author, and Michel Sadelain, senior author, both of Memorial Sloan Kettering Cancer Center. The study was supported in part by the SU2C-Cancer Research Institute Cancer Immunology Dream Team.
“In this phase I clinical trial, intrapleurally administered MSLN-targeted CAR T-cells had no evidence of ‘on-target, off-tumor’ or therapy related toxicity, and there was evidence of CAR T-cell antitumor activity,” the authors reported. “MSLN-targeted CAR T-cell therapy combined with anti-PD1 agents shows encouraging clinical outcomes, thus a combination therapy trial is planned to recruit patients in the second quarter of 2019.
The trial was supported by the St. Baldrick’s Foundation-SU2C Pediatric Cancer Dream Team, among others. Shoba Navai of Baylor College of Medicine is first author. Also, at Baylor are Meenakshi Hegde, senior author; a young investigator on the Dream Team and a 2017 SU2C Innovative Research Grant recipient, and Nabil Ahmed, principal investigator on the trial and a principal investigator on the Dream Team.
The authors concluded: “Administration of lymphodepletion chemotherapy followed by autologous HER2-CAR T-cells is safely tolerated and is associated with objective clinical benefit in some patients with advanced HER2+ sarcoma. Immune correlative studies suggest that the HER2-CAR T-cells given in combination with Flu/Cy lymphodepletion induce endogenous immune reactivity. These findings warrant further evaluation in a phase II study as a single agent or in combination with other approaches.”
Imvax announce positive results from clinical trial of IGV-001 vaccine in glioblastoma
Imvax Inc. announced positive results from an ongoing phase Ib clinical trial that demonstrate treatment with IGV-001, the company’s novel autologous tumor cell vaccine, outperformed standard of care with prolonged overall survival and progression-free survival in patients with newly diagnosed glioblastoma multiforme.
The results, which were presented today in an oral presentation during the Advances in Novel Immunotherapeutics session at the American Association for Cancer Research Annual Meeting 2019, support the continued development of a new immunotherapy paradigm for the treatment of GBM.
The phase Ib trial evaluated the safety and efficacy of IGV-001, an autologous vaccine made from patients’ tumor cells and an antisense formulation, in adults with newly diagnosed GBM. Thirty-three patients received one of four vaccine exposures.
SOC treatment (radiotherapy and temozolomide) was initiated four to six weeks after vaccine administration. The primary endpoint was safety and the secondary endpoint was tumor response. Exploratory objectives included assessment of PFS, OS and immune markers. A historical comparator group comprised of 35 newly diagnosed GBM patients treated at the same center evaluated SOC alone.
Treatment with IGV-001 was well tolerated, and 15 of 33 patients (45.5%) experienced no tumor growth as of March 1. Moreover, the cohort treated with the highest vaccine dose demonstrated an improvement of 7.3 months in OS (21.9 months vs. 14.6 months per Stupp) and 3.5 months in PFS (10.4 months vs. 6.9 months when compared against the historical comparator group; p=0.031) against SOC treatment alone.
The most prominent survival statistics included those patients with DNA methylation of the MGMT promoter which favors temozolomide treatment. However, PFS for methylated patients was three-fold longer (30.9 months vs. 10.3 months for historic SOC patients per Hegi). This finding is under further investigation for its benefit.
IGV-001 has been developed over the past 20 years at Thomas Jefferson University Hospital in Philadelphia, where three phase I trials directed by Andrews and Hooper have now demonstrated efficacy and safety.
IGV-001 is a first-in-class autologous vaccine in development for the treatment of newly diagnosed glioblastoma multiforme, a lethal and common type of brain tumor. Based on early clinical research, one treatment with IGV-001 has the potential to trigger a multi-pronged immune response, including a short-term innate immune response followed by longer-term powerful adaptive immune activity, that is selectively directed at the patients’ tumor cells.
IGV-001 has been granted orphan drug designation for the treatment of malignant glioma by FDA and the European Medicines Agency.
ADMIRAL trial data Shows Xospata prolongs OS in adults with leukiemia
Astellas Pharma Inc. announced results from the phase III ADMIRAL clinical trial comparing Xospata (gilteritinib) to salvage chemotherapy in adult patients with relapsed or refractory acute myeloid leukemia with a FLT3 mutation.
The results show that patients treated with Xospata had significantly longer overall survival than those who received standard salvage chemotherapy. The data were shared by Alexander Perl, Abramson Cancer Center, University of Pennsylvania, in a press conference at the American Association for Cancer Research annual meeting.
Results from the ADMIRAL trial show the median OS for patients who received Xospata was 9.3 months compared to 5.6 months for patients who received salvage chemotherapy (Hazard Ratio = 0.637 (95% CI 0.490, 0.830), P=0.007); one-year survival rates were 37% for patients who received Xospata compared to 17% for patients who received salvage chemotherapy.
Xospata was approved by the FDA in November 2018 for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.
Xospata was discovered through a research collaboration with Kotobuki Pharmaceutical Co., and Astellas has exclusive global rights to develop, manufacture and commercialize Xospata.
Xospata was approved by the Japan Ministry of Health, Labor and Welfare for relapsed or refractory AML with FLT3 mutations and launched as Xospata 40 mg Tablets in 2018.
In February 2019, a marketing authorization application for the oral once-daily therapy Xospata for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation was accepted by the European Medicines Agency for regulatory review.
Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several phase III trials.
The phase III ADMIRAL trial (NCT02421939) was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy.
The primary endpoint of the trial was overall survival. The study enrolled 371 patients with relapsed or refractory AML and positive for FLT3 mutations present in bone marrow or whole blood. Subjects were randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.
Single agent umbralisib effective for relapsed slow-growing lymphoma
A study at MD Anderson Cancer Center revealed the investigational drug umbralisib as an effective treatment for patients with relapsed marginal zone lymphoma. Findings from the phase II trial were presented by study co-lead Nathan Fowler, associate professor in the Department of Lymphoma & Myeloma, at the AACR Annual Meeting 2019 in Atlanta.
“Umbralisib is part of a new class of drugs that are quite active in low-grade lymphomas,” said Fowler. “These PI3K inhibitors have shown activity across a spectrum of low-grade lymphomas and are effective in shutting down some of the key signaling that is occurring with MZL.”
The research team reported 55% of patients who had at least six months of follow-up had a partial or complete response after receiving umbralisib, a small-molecule inhibitor that targets a signaling pathway linked to MZL cell growth and expansion. Felipe Samaniego, associate professor in Lymphoma & Myeloma, was co-lead for the study.
The trial enrolled 69 patients, with 38 patients responding favorably and progression-free survival was 71% after one year. The patients received umbralisib orally once a day.
“This study is ongoing and we have yet to reach a median duration of response, although most of the patients who received the drug remain in remission,” said Fowler.
The average MZL patient is diagnosed at about age 60 and is typically treated with a monoclonal antibody called rituximab either alone or in combination with chemotherapy.
“This disease is initially quite treatable with several good options for patients that result in high response rates,” said Fowler. “Unfortunately, for about 70% of these patients, relapse occurs and there are limited treatment options at that time. That relapse can occur within a year or it can take several years, but most patients will eventually stop responding to standard treatment.”
Fowler’s team was specifically looking at patients who had failed several standard treatment options including chemotherapy or monoclonal antibodies.
“At MD Anderson, we have been fortunate to lead the development of several of these targeted drugs in lymphoma,” he said. “Phase I studies conducted here with PI3K and BTK inhibitors has now resulted in FDA approval of many of these drugs across several types of lymphoma.”
Study names six risk factors linked to esophageal cancer
The north-eastern region of the Islamic Republic of Iran has some of the highest rates of esophageal cancer anywhere in the world. New results from an international prospective study of 50,000 individuals, recently published online in the journal Gastroenterology, provide evidence on how the combined effects of six main risk factors are responsible for the high rates of esophageal cancer in this region.
The results are based on more than 10 years of follow-up of 50,000 individuals as part of the Golestan Cohort Study, which was initiated in 2004 by the Digestive Diseases Research Institute of the Tehran University of Medical Sciences, the International Agency for Research on Cancer, and NCI.
The six most important risk factors identified were drinking hot tea, smoking opium, low intake of fruits and vegetables, drinking unpiped water, exposure to indoor air pollution, and excessive tooth loss.
The study found that about three quarters of the esophageal cancer cases in the north-eastern region can be attributed to a combination of exposures to the identified risk factors, which are all preventable through education and by improving basic social infrastructure.
The GCS is the largest prospective study of its kind in central and western Asia. It was established to provide a major resource for studying esophageal cancer, through the collection of biological samples and detailed assessments of diet, lifestyle, and different exposures, at enrolment and then every 5 years.
Instead of relying only on self-reported information, the GCS was the first study to also make objective measurements of the suspected risk factors for oesophageal cancer, including the actual temperature at which tea is drunk, and carry out precise oral examinations.
“The GCS was initiated in an area where esophageal cancer constituted about 25% of the reported cancer cases, and the study has made important contributions to the discovery and development of the scientific information on the risk factors for upper gastrointestinal cancers and other noncommunicable diseases,” Reza Malekzadeh, director of the Digestive Diseases Research Institute of the Tehran University of Medical Sciences and is the principal investigator of the GCS, said in a statement.
“The GCS represents a major and long-standing collaboration between scientists in the Islamic Republic of Iran, IARC, and NCI, and it is an important representation of how medical research can overcome political and economic barriers,” Paul Brennan, head of the Section of Genetics at IARC and is a co-principal investigator of the GCS, said in a statement.
“This study shows how the combination of the risk factors can substantially increase the risk of oesophageal cancer, and strongly suggests that esophageal cancer in high-incidence areas is a multifactorial disease, requiring a combination of exposures for its development. Therefore, this study has important implications for public health and policy, and will aid the translation of knowledge and the implementation of evidence into practice and policy decision-making.”
Probiotics linked to poorer response to cancer immunotherapy in skin cancer
In melanoma patients, taking over-the-counter probiotic supplements was associated with a 70% lower chance of response to cancer immunotherapy treatment with anti-PD-1 checkpoint inhibitors, according to a preliminary study from the Parker Institute for Cancer Immunotherapy and MD Anderson Cancer Center. The results were presented at the American Association for Cancer Research 2019 Annual Meeting in Atlanta.
Researchers also found that probiotics were linked to lower diversity in the gut microbiome, previously found to be associated with poorer immunotherapy response.
“These findings about probiotics were a bit surprising to us because the general perception is they make your gut microbiome healthier,” first author Christine Spencer, a research scientist at the Parker Institute, said in a statement. “While more research is needed, our data suggests that may not be the case for cancer patients.”
Probiotics are not regulated by FDA.
“Based on our early results, cancer patients and doctors should carefully consider the use of over-the-counter probiotic supplements, especially before beginning immunotherapy treatment,” said senior author Jennifer Wargo, a PICI investigator at MD Anderson.
This is the first clinical study designed to examine the relationships between diet, the gut microbiome and immunotherapy response in cancer patients. In addition to the probiotics findings, the data also show patients who reported eating a high-fiber diet were five times as likely to respond to cancer immunotherapy.
The implications of the research are significant because checkpoint inhibitors—a Nobel Prize-winning type of cancer immunotherapy treatment—only work for 20 to 30% of cancer patients.
The research bolsters the idea that cancer patients might be able to improve how well immunotherapy treatment works by eating, drinking, or avoiding certain foods, beverages and supplements.
“Imagine if you could increase the number of patients who benefit from immunotherapy through something as simple as dietary changes. That would be remarkable,” Spencer said. “It’s probably not going to be that simple, as there are many factors at work. But this study does point to diet playing a role in immunotherapy response via the gut microbiome and we hope these findings will spur more studies on this topic in the cancer research community.”
In recent years, scientists have discovered that the trillions of intestinal microbes that make up the gut microbiome exert significant control over the immune system. Cancer immunotherapy drugs such as checkpoint inhibitors work by engaging the immune system to fight off cancer.
In theory, the makeup of the microbiome could affect the immune system, and in turn, the ability for immunotherapy to work against cancer.
A prior study by Wargo and Spencer was one of the first to explore that idea. In their 2018 Science paper, they and colleagues at MD Anderson found that a more diverse array of microbes in the gut was associated with better response to checkpoint inhibitors for cancer, and that certain types of bacteria in the Ruminococcaceae family were associated with a better response to anti-PD-1 checkpoint inhibition. Other types of bacteria, such as those in the order Bacteroidales, were linked to a poorer outcome.
“There were different types of microbiome profiles, if you will, that were linked to better or poorer response to checkpoint inhibition,” Wargo said in a statement. “For this new study on the diet, microbiome and immunotherapy, we used profiles of responders as the mark of a “good” microbiome when it comes to immunotherapy response.”
The prospective study involved 113 metastatic melanoma patients who were starting treatment at MD Anderson. The researchers prospectively evaluated their microbiomes by sequencing their fecal samples to determine the presence and abundance of various bacteria in the gut. Patients were also asked to take a lifestyle survey to report on their diet and use of supplements and medication.
After following patients through treatment, the researchers found several correlations between dietary factors and the gut microbiome. They also evaluated those factors in relation to immunotherapy response in a subset that went on anti-PD-1 checkpoint inhibitors.
Overall, Parker Institute and MD Anderson researchers found that diet and supplements appear to have an effect on a patient’s ability to respond to cancer immunotherapy, most likely due to changes in the patient’s gut microbiome.
Among the findings:
Over-the-counter probiotic supplement use was linked to a 70% lower chance of response to immunotherapy with anti-PD-1 checkpoint inhibitors in a subset of 46 melanoma patients
42% of all patients reported taking over-the-counter probiotics among those who took the lifestyle survey
Probiotics were linked to lower gut microbiome diversity, previously shown to be associated with poorer response to anti-PD-1 checkpoint inhibitors
Patients eating high-fiber diets were about 5 times as likely to respond to immunotherapy treatment with anti-PD-1 checkpoint inhibitors
Patients eating diets rich in whole grains had more bacteria associated with positive response to checkpoint immunotherapy
Diets high in processed meat and added sugar had fewer bacteria associated with a positive response to checkpoint immunotherapy
While this study focused on correlations rather than root cause, other randomized, controlled clinical trials are underway that are designed to directly answer the question of whether one can manipulate the microbiome—through food, fecal transplant or other means—to improve cancer immunotherapy response.
The Parker Institute is now conducting such a trial in collaboration with MD Anderson and Seres Therapeutics. This randomized, placebo-controlled clinical study is evaluating whether a specially designed oral microbiome pill with specific types of bacteria could positively impact a patient’s response to checkpoint inhibitors.
The study is open at MD Anderson and the Angeles clinic. For additional information on this trial (NCT03817125) please visit clinicaltrials.gov.
In addition, a team of MD Anderson researchers is planning a prospective randomized study in which cancer patients will be provided with different types of diets. Their gut microbiomes will be sequenced to see if and how they change. The study will also evaluate treatment response to immunotherapy.
Rucaparib maintenance therapy shows clinical responses in pancreatic cancer
Maintenance treatment with the PARP inhibitor rucaparib (Rubraca) was well tolerated and provided clinical responses among patients with advanced BRCA- or PALB2- mutated pancreatic cancer sensitive to platinum-based chemotherapy, according to results from an interim analysis of an ongoing phase II clinical trial presented at the AACR Annual Meeting 2019.
Rubraca is sponsored by Clovis Oncology.
“In this interim analysis, we are finding that patients with platinum-sensitive pancreatic cancer appear to benefit from treatment with single agent rucaparib,” Kim Reiss Binder, assistant professor of medicine in the Division of Hematology Oncology at The Hospital of The University of Pennsylvania, said in a statement.
“Several patients had complete or partial responses with rucaparib treatment, suggesting that this therapy has the potential not only to maintain the disease, but also to shrink the tumors in some instances,” Reiss Binder said.
Approximately 6 to 8% of patients with pancreatic cancer harbor pathogenic mutations in the genes BRCA or PALB2, Reiss Binder said. Mutations in these genes often coincide with susceptibility to platinum-based chemotherapies, she said.
“While this subgroup of pancreatic cancer patients respond well to platinum-based chemotherapy, prolonged treatment leads to cumulative toxicity, so this approach often becomes unsustainable,” said Reiss Binder. “We wanted to investigate more tolerable maintenance options, as there are no approved treatments in this setting.”
Rucaparib was approved as a maintenance treatment for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who respond to platinum-based chemotherapy.
This single-arm, phase II clinical trial is actively enrolling patients with advanced BRCA- or PALB2-mutated pancreatic cancer who have not progressed on prior platinum-based chemotherapy. The patients in the interim analysis had received a median of four months of prior platinum chemotherapy. More than 80% of patients were female.
Patients are treated with 300mg of rucaparib twice daily until disease progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival. Overall response rate is also being evaluated.
Nineteen of the 24 enrolled patients were evaluable for analysis as of Dec. 31, 2018.
The median PFS at time of analysis was 9.1 months following initiation of rucaparib treatment. The ORR was 37%, which included one complete response and six partial responses. The disease control rate (defined as the sum of PR, CR, and stable disease) was 90% for at least eight weeks. Eight patients remained on rucaparib therapy for at least six months, and two patients have remained on rucaparib therapy for more than one year.
“Although this is very preliminary data, the fact that we’re seeing sustained clinical responses in some of these patients is very exciting,” said Reiss Binder. “Other than the recent tissue- agnostic approval of pembrolizumab for patients with microsatellite instability-high tumors, there really is no other targeted therapy that has shown promise for patients with pancreatic cancer.
“Our results highlight the importance of germline and somatic testing in pancreatic cancer patients,” said Reiss Binder. “The presence of certain mutations can guide treatment strategies, and patients should know to ask their oncologist about getting tested.”
As this was an unplanned interim analysis of an ongoing, small, single-arm study, the results require substantial further validation.
This study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.