publication date: Oct. 9, 2020
City of Hope leads novel clinical trial to treat cancer patients with COVID-19
In a new clinical trial, City of Hope is investigating a treatment for cancer patients with COVID-19 by repurposing leflunomide, an anti-inflammatory drug for rheumatoid arthritis, which is inexpensive and has few serious side effects.
Patients treated for cancer in the past two years may also be eligible.
FDA has recently approved the start of a phase I trial. At a later date, a phase II randomized clinical trial may take place if the first trial finds leflunomide to be safe and tolerable for these patients. City of Hope plans to work with other local medical centers who are treating cancer patients for SARS-CoV-2, the virus that causes COVID-19, to enroll them in the trial.
“There are currently few effective drugs against COVID-19, and our clinical trial targets a critical high-risk group — cancer patients whose immune systems are already weak,” Steven T. Rosen, City of Hope provost and chief scientific officer, and the Irell & Manella Cancer Center Director’s Distinguished Chair and Morgan & Helen Chu Director’s Chair of the Beckman Research Institute, said in a statement. “Our hope is that leflunomide will eradicate COVID-19 in cancer patients, providing the medical community with an effective therapy against this devastating virus.”
Sanjeet Dadwal, City of Hope chief of the Division of Infectious Diseases, is the principal investigator on the trial.
For the phase I trial, all patients will receive leflunomide and may also be able to simultaneously receive other standard of care treatments for COVID-19. They may receive remdesivir, an antiviral therapy. Patients with acute respiratory distress syndrome may receive the steroid, dexamethasone, and patients with complications of COVID-19 such as cytokine release syndrome, which can lead to multiple organ failure, can receive the antibody tocilizumab.
If the phase I trial is found to be a safe and tolerable treatment, then a phase II randomized, double-blind trial will open at a later date. About half the patients will receive leflunomide with standard of care therapies to treat COVID-19, and the other half will receive a placebo and standard of care drugs as well.
Leflunomide is an oral and generic anti-inflammatory drug approved by FDA to safely treat autoimmune diseases such as rheumatoid arthritis. The therapy has also been used in cancer patients with cytomegalovirus with tolerable side effects.
Laboratory experiments performed at City of Hope and Wuhan, China, indicate that leflunomide has high potential to shut down viral replication by preventing the synthesis of viral RNA, the genetic material. It also downregulates the expression of ACE 2, a receptor for COVID-19 cell entry. A small clinical trial using leflunomide in China also demonstrated the therapy has potential antiviral drug against COVID-19.
In a phase I clinical study, City of Hope treated patients with advanced multiple myeloma with leflunomide. The therapy stabilized their disease with tolerable side effects.
NCI has funded the trial with a P30 grant supplement for COVID-19 research projects. City of Hope is one of a few cancer centers that has received such funding during the pandemic.
City of Hope also received funding from private donors, including The Elias, Genevieve and Georgianna Atol Charitable Trust and The Norman and Sadie Lee Foundation.
Novel CAR T-cell lymphoma therapy developed at MCW advances to phase II study
A novel cancer therapy studied and developed at the Medical College of Wisconsin with promising clinical outcomes is leading to a larger phase II trial to improve on the current standard of care.
Results of phase I of the first-in-the-world double targeted CAR T-cell therapy clinical trial were published in Nature Medicine.
This is a novel, cell-based treatment against cancer targeting two proteins (antigens CD19 and CD20) on the surface of cancer cells. This CAR T-cell therapy trial began in October 2017 and resulted in safe and promising outcomes for patients with relapsed and refractory B cell non-Hodgkin lymphomas which are cancers of the immune system.
MCW researchers collected patient T cells and then used a specially engineered virus to augment their ability to identify and kill cancerous cells and effectively destroy the lymphoma. While phase I focused on safety and feasibility of the treatment, a multi-institutional phase II is being developed to determine the true efficacy and understand how the nuances of the treatment process can result in excellent outcomes for a larger subset of patients.
All patients in the clinical trial had failed prior treatments and their cancer had relapsed. Within 28 days of the CAR-T cell therapy, 82 percent responded positively. Six months later, more than half of the patients’ cancer remained in remission. A higher dose of the treatment correlated with a prolonged remission, a trend the researchers plan to study further in the trial’s second phase.
The new treatment genetically alters a person’s own immune cells to target cancer cells in a unique and personalized fashion, a significant departure from more routine chemotherapy.
The cell product used for treatment was manufactured using the CliniMACS Prodigy device, which is part of an automated CAR T cell manufacturing platform developed by Miltenyi Biotec.
Housed at the Froedtert & MCW Clinical Cancer Center, the CliniMACS Prodigy device enabled the research team to conduct the CAR T-cell immunotherapy through a self-contained, desktop system, producing new cells ready to be infused back into a patient’s bloodstream within 14 days. With the device, the entire process was performed locally at Froedtert Hospital.
This research was made possible through philanthropic dollars raised by the Children’s Wisconsin Foundation and the MACC Fund and their support of the Cell Therapy Lab at MCW.
MD Anderson researchers identify characteristics of infused CAR T cells associated with efficacy and toxicity in large B-cell lymphoma
Researchers at MD Anderson Cancer Center have identified molecular and cellular characteristics of anti-CD19 CAR T cell infusion products associated with how patients with large B-cell lymphoma respond to treatment and develop side effects.
The research team also found that early changes in circulating tumor DNA one week after CAR T cell therapy may be predictive of treatment response in a particular patient. The paper was published online in Nature Medicine.
“CAR T cell therapy is highly effective against LBCL,” corresponding author Michael Green, associate professor of lymphoma and myeloma, said in a statement. “However, we experience two main clinical challenges: achieving long-term remission and managing treatment-associated adverse events.”
This study suggests that, within the first week of therapy, clinicians may be able to identify a subset of patients who may experience more poor outcomes or adverse treatment reactions, said Green. This would allow the care team to adjust therapy to improve efficacy or to act to mitigate toxicity.
For this study, researchers performed single-cell analysis on CAR T cells to study gene expression profiles in the infused cells. CAR T cells were collected from those remaining in infusion bags following treatment of 24 patients with LBCL. These genetic profiles were compared to treatment responses, determined at three months post-infusion by PET/CT scan.
“When we look at the characteristics of the infused CAR T cells, we found that samples from patients who were less responsive to treatment had exhausted T cells, whereas those who experienced complete responses had T cells expressing ‘memory’ signatures,” co-corresponding author Sattva Neelapu, professor of lymphoma and myeloma, said in a statement. “Additionally, one cellular signature of T cell exhaustion was more commonly found in patients who exhibited a poor molecular response, and poor molecular response is generally associated with less-positive, long-term outcomes.”
Further, the researchers analyzed early molecular responses in the patients by monitoring changes in circulating tumor DNA from treatment to one week post-infusion. The magnitude of change in tumor-associated DNA corresponded with response, suggesting that patients who displayed an early molecular response were more likely to experience a clinical response to treatment.
“When we examined the infusion product, we found that a cell population with characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with development of high-grade neurotoxicity,” Green said. “Detecting these cells may subsequently lead us to identify patients who would be at higher risk of developing neurotoxicity, allowing us to provide prophylactic treatment with agents that target the specific cellular features.”
Further examination may lead to insights into the types and attributes of the cells present within the CAR T infusion product.
“This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important,” said co-corresponding author Linghua Wang, assistant professor of Genomic Medicine. “Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.”
These findings will help researchers develop clinical interventions that can block or target these cells. They also plan to validate the capacity of circulating tumor DNA to accurately predict patients’ long-term outcomes.
This research was supported in part by the B-cell Lymphoma Moon Shot, part of MD Anderson’s Moon Shots Program. With support from the Moon Shot and the Cancer Prevention & Research Institute of Texas, the research team plans to utilize PDX models of disease that relapsed following anti-CD19 CAR T cell therapy to preclinically test interventions that could lead to better treatment responses or to prevention of adverse side effects.
Other research support came from the Schweitzer Family Fund, NCI (P30 CA016672) and start-up research funds from MD Anderson. A full list of co-authors and their disclosures can be found here.
MD Anderson researchers: Cancer mutations accumulate in distinct regions based on structure of genome and mutational causes
A study from researchers at MD Anderson Cancer Center indicates that mutations found in cancers do not accumulate randomly, but are found in distinct patterns that vary based on the three-dimensional organization of the genome in the cell as well as the underlying factors causing the mutations.
Mutations caused by external factors, such as ultraviolet light or tobacco smoke, led to mutations in different regions than internal factors, such as defects in DNA damage repair or proofreading machinery. The findings, published in Nature Genetics, are important for understanding what factors may be driving mutations in a given cancer and may point to new therapeutic targets.
“DNA is not randomly organized within the nucleus, and we found that this structure is strongly correlated with how cancer cells accumulate mutations,” lead author Kadir Akdemir, instructor of genomic medicine, said in a statement. “We know there are certain processes causing mutations in cancer cells, but we don’t always understand the underlying causes. These findings should give us a clue as to how cancer accumulates mutations, and perhaps we can target and kill cancer cells by leveraging the mutations they accumulate.”
Within the nucleus of the cell, DNA is packaged with proteins into chromatin, a highly organized and compacted structure that makes up our chromosomes. Within this structure, genes that are frequently used in the cells are organized together in “active domains,” which are more readily accessible. Those genes used less often are similarly organized together in “inactive domains.”
The researchers analyzed whether mutations are distributed more frequently in these active or inactive domains in cancer by studying publicly available whole-genome sequencing data of 3,000 paired samples of normal tissue and tumor tissue across 42 cancer types.
Across every cancer type studied, the inactive domains carried significantly more mutations than the active domains, suggesting that the accumulation of mutations is strongly correlated with the three-dimensional organization of the genome.
As a validation of these findings, the researchers looked specifically at the X chromosome in male and female patients. In females, one of their two X chromosomes is inactivated, so it is essentially itself an inactive domain. When comparing the X chromosome between sexes, females had more mutations than males with a marked distribution difference, largely driven by an abundance of mutations on the inactive chromosome.
Knowing that mutations can be caused by a variety of distinct processes, the researchers also investigated whether external environmental factors resulted in different mutation patterns compared to those caused by internal factors in the cell.
“Interestingly, we found that different causes of mutations resulted in distinct accumulation patterns within the cell,” senior author Andy Futreal, chair of genomic medicine, said in a statement. “Extrinsic factors were associated with an enrichment of mutations in inactive domains, whereas intrinsic factors were correlated with enriched mutations in active domains. This provides us an important foundation going forward to understand the root of cancer mutations when we don’t otherwise know the cause.”
Knowing the causes and distributions of cancer-related mutations may open up potential therapeutic options, explained Akdemir, such as targeted therapies against a specific signaling pathway or combinations with immunotherapy.
For example, immunotherapy may be able to better recognize a cancer cell if more mutations are present. However, if mutations occur primarily in inactive domains, they would rarely be seen by the immune system. Therapeutic agents that restore activity to these domains, used in combination with immune checkpoint inhibitors, could stimulate a stronger anti-tumor immune response.
This research was supported by the Cancer Prevention & Research Institute of Texas (R1205), The Robert A. Welch Distinguished University Chair in Chemistry, and NIH (P50CA127001, DP5OD023071, Z1AES103266). A full list of authors and their disclosures can be found with the full paper here.
UCSD study: Personalized cancer therapy improves outcomes in advanced disease
Researchers at the University of California San Diego School of Medicine found that patients receiving care for advanced cancer at Moores Cancer Center at UC San Diego Health were more likely to survive or experience a longer period without their disease progressing if they received personalized cancer therapy.
The study was published in Nature Communications.
Led by Razelle Kurzrock, director of the Center for Personalized Cancer Therapy at Moores Cancer Center and senior author of the study, a multidisciplinary molecular tumor board was established to advise treating physicians on course of care using an individual patient’s molecular tumor makeup to design precision medicine strategies.
“Patients who underwent a molecular tumor board-recommended therapy were better matched to genomic alterations in their cancer and had improved outcomes,” Kurzrock said in a statement. “The three-year survival for patients with the highest degree of matching and who received a personalized cancer therapy was approximately 55% compared to 25% in patients who received therapy that was unmatched or had low degrees of matching.”
Of 429 patients evaluated by the molecular tumor board, 62% were matched to at least one drug. Twenty percent of patients matched to all recommended drugs, including combination therapies.
The tumor board acted in an advisory role and treating physicians chose not to use the board’s recommended strategy in 38% of cases, opting instead for a standard therapy approach that might have been unmatched to the patient’s genetic alterations or had a low degree of matching. These patients experienced a lower progression-free survival and overall survival rates.
The use of next-generation sequencing allows for the identification of novel potential targets for patients with cancer to improve outcomes, but there are challenges to using this approach widely, said Shumei Kato, associate professor of medicine at UC San Diego School of Medicine and first author.
“One of the hurdles is that every cancer patient appears to be carrying different molecular and genomic patterns despite having the same cancer type,” Kato, a Moores Cancer Center medical oncologist specializing in rare and gastrointestinal cancers, said in a statement. “This can be challenging since we are customizing therapy based on the unique genomic pattern patients have, and thus it is difficult to predict the response. In addition, this approach requires multidisciplinary expertise as well as access to drugs or clinical trials not always available in smaller practices.”
At Moores Cancer Center, the molecular tumor board is composed of experts in basic, transitional and clinical research as well as bioinformatics, genetics, radiology, pathology and physicians in multiple specialties such as medical, surgical and radiation oncology.
This research was funded, in part, by NIH (P30 CA023100) and the Joan and Irwin Jacobs Fund.
Phase III CheckMate-816 trial: Opdivo + chemotherapy demonstrates improvement in pathologic CR in resectable NSCLC
The phase III CheckMate-816 trial met a primary endpoint of pathologic complete response in resectable non-small cell lung cancer.
In the trial, significantly more patients treated with Opdivo (nivolumab) plus chemotherapy before surgery showed no evidence of cancer cells in their resected tissue compared to those treated with chemotherapy alone. CheckMate-816 is the first and only phase III trial to demonstrate a benefit with an immune checkpoint inhibitor in combination with chemotherapy as a neoadjuvant treatment in non-metastatic NSCLC.
Opdivo is sponsored by Bristol Myers Squibb.
Patients in the experimental arm of the trial received up to three doses of Opdivo plus chemotherapy prior to surgery, a standard number of cycles of therapy in the neoadjuvant setting. The safety profile of Opdivo plus chemotherapy was consistent with previously reported studies in NSCLC.
“Nivolumab has shown benefit as an adjuvant, or post-surgical, treatment option in other cancer types, and the positive results from CheckMate -816 speak to its potential in the neoadjuvant setting of resectable non-small cell lung cancer,” Mark Awad, clinical director of Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said in a statement.
The CheckMate-816 trial is ongoing to assess the other primary endpoint of event-free survival, to which the company remains blinded, as well as key secondary endpoints.
In non-metastatic NSCLC, Bristol Myers Squibb and collaborators are exploring the use of immunotherapy in the neoadjuvant, adjuvant and peri-operative settings, as well as in association with chemoradiation. To date, Opdivo has shown improved efficacy in the neoadjuvant or adjuvant treatment of four tumor types: lung cancer, bladder cancer, esophageal/gastroesophageal junction cancer and melanoma.