publication date: Feb. 5, 2021

Clinical Roundup

More than half of cancer survivors have underlying medical conditions associated with severe COVID-19

More than half (56.4%) of cancer survivors in the United States reported having additional underlying medical conditions associated with severe COVID-19 illness.

The report appears in JNCI: The Journal of the National Cancer Institute, and suggests that prevalence of these conditions among cancer survivors is nearly 40% higher than that in the general population.

Cancer, and other underlying medical conditions, including chronic obstructive pulmonary disease, heart diseases, diabetes, chronic kidney disease, and obesity, are associated with increased risk of severe COVID-19 illness.

For this study, investigators Changchuan (Charles) Jiang, of Roswell Park Comprehensive Cancer Center, Xuesong Han, of American Cancer Society, and colleagues used data from the 2016-2018 National Health Interview Survey, a national cross-sectional survey of the civilian, noninstitutionalized population, to examine the prevalence of underlying medical conditions associated with severe COVID-19 Illness in adult cancer survivors in the U.S.

“This study investigates the prevalence and factors associated with these underlying medical conditions among cancer survivors in the U.S. We felt it was important to compile and analyze the available data to inform the public and guide the policy makers on opportunities to prevent and control severe COVID-19–associated illness through strategies such as risk-stratified vaccine distribution,” Jiang said in a statement.

Most cancer survivors reported having more than one of the conditions associated with severe COVID-19 illness and nearly one-quarter reported more than two conditions. These conditions were more prevalent in survivors of kidney, liver and uterine cancers, as well as Black survivors, those with low socioeconomic status, and public insurance.

Older age was associated with higher prevalence of medical conditions among cancer survivors and adults without a cancer history. However, even in the youngest age group (18 to 44 years), nearly half of cancer survivors (47.6%) had at least one additional condition associated with severe COVID-19 illness.

In addition to increasing prevalence with age, medical conditions were more prevalent among male survivors (59.9%), those with less than high school completion (68.0%), non-Hispanic Black (67.2%), low income (71.7%), and those living in the South (59.2%).

 

Gene mutations linked to worse outcomes from leukemia in Hispanic and Latino children

A combination of genetic mutations may explain the higher incidence of and poorer outcomes from pediatric leukemia in Hispanic and Latino children, according to Penn State College of Medicine researchers.

A novel therapeutic drug combination, as well as testing for these mutations, may help address the disparity. The findings were published in Leukemia.

Hispanic and Latino children are between 1.2 and 1.75 times more likely to develop B-cell acute lymphoblastic leukemia, the most common childhood cancer, than non-Hispanic and Latino children. They also have a 40% higher death rate than their counterparts after correcting for socioeconomic factors.

Sinisa Dovat, a researcher and pediatric oncologist at Penn State Children’s Hospital and Penn State Cancer Institute, partnered with Dr. Gordana Raca of Children’s Hospital Los Angeles and Kimberly J. Payne of Loma Linda University to understand the biology behind this health disparity after prior research suggested that there may be an increased frequency of a type of genetic mutation in Hispanic and Latino children with B-ALL.

The researchers studied 239 pediatric patients with B-ALL at Children’s Hospital Los Angeles and found two types of genetic mutations—deletion of the IKZF1 gene (IKZF1) which holds instructions for cells to make the IKAROS protein and a rearrangement, or translocation, of the gene with instructions for producing the CRLF2 protein—occurred more frequently in Hispanic and Latino children.

IKZF1 deletion occurred two times more frequently in those children—making it the most frequent genetic alteration that signals poor prognosis of B-ALL. There was a four-fold increased incidence of CRLF2 translocations in Hispanic and Latino children, as compared to non-Hispanic and Latino children.

“These mutations offer an explanation for the poor prognosis and increased incidence of B-ALL in Hispanic and Latino children and offer us insight into this pediatric cancer health disparity,” Dovat said in a statement.

The researchers found that 11% of Hispanic and Latino children had both mutations compared to 0% of their counterparts. Almost all of the Hispanic and Latino children with B-ALL who had a specific type of CRLF2 translocation also had an IKZF1 deletion, while a large number of them had an IKZF1 deletion without that specific type of CRLF2 translocation. According to Dovat, these results suggest that IKZF1 deletion precedes or predisposes the CRLF2 gene to mutation.

“Sequencing these genes in Hispanic and Latino children with B-ALL is essential to help pediatric oncologists determine a prognosis for these patients and develop appropriate treatment plans,” Dovat said. “Treatments that can restore the function of the IKAROS protein could be an efficient treatment for leukemia.”

In a companion study, also published in Leukemia, Dovat and colleagues outlined a treatment strategy that may be beneficial to patients suffering from this health disparity. It involves targeting a protein, mTOR, that when over produced, can lead to resistance to chemotherapy and poor prognosis.

“The CRLF2 mutation, often found in Hispanic and Latino children with B-ALL, leads to increased activity of mTOR, which has been associated with poor outcomes,” Dovat said. “We proposed that an effective treatment regimen would hinder the activity of the mTOR protein, but also target the gene that carries the instructions for making mTOR by restoring the function of the IKAROS protein.”

The researchers developed a combination therapy, starting with a drug that restores the function of IKAROS by inhibiting another protein called casein kinase 2 (CK2). When CK2 is prevented from carrying out its function, the IKAROS protein can keep mTOR from being produced. The team also used rapamycin to inactivate mTOR proteins already present in cancer cells.

Dovat and his colleagues evaluated this approach in the lab by using the combination, and each drug individually, on cancer cells from Hispanic and Latino patients. They also later tested the approach against each drug individually and in combination in an animal model of leukemia using cancer cells from Hispanic and Latino pediatric B-ALL patients.

They found that in both instances, the combination of two drugs proved more effective against leukemia than either drug individually. These studies laid the groundwork for a phase I clinical trial with this treatment and provided a new paradigm for similar approaches to treat cancer using dual targeted treatments.

 

Queen’s leading new research aimed at improving outcomes for early-stage bowel cancer

Researchers from the Patrick G Johnston Centre for Cancer Research at Queen’s University Belfast are leading an international consortium that aims to determine better ways to treat patients diagnosed with the earliest stages of bowel cancer.

The consortium is funded by Cancer Research UK.

The consortium includes a multi-disciplinary team of research scientists and clinicians from across the UK and Europe and is led by Philip Dunne, molecular pathologist at the Patrick G Johnston Centre for Cancer Research.

There are approximately 1.4 million cases of bowel cancer diagnosed worldwide every year and the introduction of the bowel cancer screening program for people over the age of 60 has led to a significant increase in the proportion of patients who are diagnosed with early-stage cancers.

Survival rates for patients diagnosed at the earliest stage of bowel cancer are in excess of 95%, but only in a small proportion of cases, screening identifies patients with highly aggressive tumors. This presents a major challenge in the clinic, as current diagnostic techniques are unable to distinguish these aggressive tumors that require more extensive in-patient treatment, from patients with less aggressive tumors that can be treated as outpatients.

“This new project aims to use state of the art molecular technologies to identify for the first time the underlying biology of these aggressive born-to-be-bad tumors,” Dunne said in a statement. “This information can be used to develop clinical biomarkers of aggressive disease that can be used to guide treatment decision making for patients in the future.”

The bowel cancer screening program is freely available to everyone over the age of 60, with a test being sent to your home every two years. The test is designed for people who have no symptoms and can detect very early signs of bowel cancer, sometimes up to 10 years before the development of advanced disease.

In a lot of cases the screening test can identify non-cancerous polyps in the bowel, which, if left unchecked, may become cancerous over time.

“Our consortium aims to improve our understanding of how these tumors grow and develop, with results being used to guide the development of clinical trials in the near future,” Maurice Loughrey, consultant pathologist at the Belfast Health and Social Care Trust and co-investigator within the consortium, said in a statement.

The initial phase of the Cancer Research UK-funded project will run until 2023, and work has already begun to collect clinical samples from across Europe to be centralised in Belfast for molecular profiling and analysis. Following this initial phase, the teams of scientists will continue to collect and analyse data over the coming years to ensure that clinicians have as much information as possible to inform treatment decisions.

“This work will provide us with the largest known collection of early-stage bowel cancer samples, which will serve as an important resource for scientists worldwide to investigate this disease,” Keara Redmond, researcher from the Patrick G Johnston Centre for Cancer Research at Queen’s, scientific specialist and project manager in Belfast, who will lead the molecular profiling, said in a statement. “This will enable the field to identify changes in tumor DNA, both mutations and gene activation, associated with aggressive disease.”

While the bowel cancer screening program has been significantly affected due to COVID-related delays, it remains an important tool for preventing deaths from bowel cancer.

 

Yale Cancer Center researchers discover mechanism to overcome drug-resistance in B-ALL

Researchers at Yale Cancer Center have discovered a novel metabolic gatekeeper mechanism for leukemia.

This mechanism depends on a molecule called PON2, which could lead to a new treatment for the disease. The findings were published in the Proceedings of the National Academy of Sciences.

In this study, Yale scientists identified high expression levels of the detoxifying lactonase PON2 in B-cell acute lymphoblastic leukemia cells as an unexpected mechanism to facilitate the energy production to promote leukemic transformation. PON2 enables glucose-uptake activity of the glucose transporter 1 by releasing the transporter from its inhibitor, stomatin.

“PON2 was critical for glucose uptake and energy production, and loss of PON2 prevented leukemia development,” senior author Markus Müschen, director of the Center of Molecular and Cellular Oncology and Arthur H. and Isabel Bunker Professor of Medicine (Hematology) at Yale Cancer Center, said in a statement. “High levels of PON2 did not only predict poor outcomes of leukemia patients in clinical trials, but it also contributes to a more aggressive course of disease.”

Researchers noted findings from this study provide new insights into B-cell metabolism as well as B-ALL biology and highlights the significance of glucose and energy supply in leukemic transformation. “From a treatment perspective, the study suggests that the enzyme activity of PON2 can be leveraged to selectively kill B-ALL cells,” Müschen said. “Targeting of PON2 could be developed as a novel therapeutic intervention strategy to overcome drug-resistance in B-ALL.”

  

IU cancer center researchers discover how breast cancer cells hide from immune attack

Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center have identified how breast cancer cells hide from immune cells to stay alive. The discovery could lead to better immunotherapy treatment for patients.

Xinna Zhang and colleagues found that when breast cancer cells have an increased level of a protein called MAL2 on the cell surface, the cancer cells can evade immune attacks and continue to grow. The findings were published in The Journal of Clinical Investigation.

“Like other cancer cells, breast cancer cells present tumor-specific antigens on the cell membrane, which immune cells recognize so they can kill the tumor cells,” lead author Zhang said in a statement. “But our study found that MAL2 can reduce the level of these antigens, so these tumor cells are protected and can no longer be recognized as a threat by these immune cells.”

Zhang is a member of the IU Simon Comprehensive Cancer Center and assistant professor of medical and molecular genetics at IU School of Medicine.

Understanding how cancer cells avoid immune attacks could offer new ways to improve immunotherapy for patients, Xiongbin Lu, Vera Bradley Foundation Professor of Breast Cancer Innovation and cancer center researcher.

The collaborative research team set out to answer key questions: How do breast cancer cells develop this immune evasion mechanism, and could targeting that action lead to improved immunotherapies?

Zhang and Lu, members of the Vera Bradley Foundation Center for Breast Cancer Research, turned to biomedical data researcher Chi Zhang, assistant professor of medical and molecular genetics at IU School of Medicine. Chi Zhang developed a computational method to analyze data sets from more than 1,000 breast cancer patients through The Cancer Genome Atlas.

That analysis led researchers to MAL2; it showed that higher levels of MAL2 in breast cancer, and especially in triple-negative breast cancer, was linked to poorer patient survival.

“Chi Zhang used his advanced computational tool to build a bridge that connects cancer genetics and cancer genomics with a clinical outcome,” Lu said in a satement. “We can analyze molecular features from thousands of breast tumor samples to identify potential targets for cancer immunotherapy. From that data, MAL2 was the top-ranked gene that we wanted to study.”

Xinna Zhang took that data to her lab to determine MAL2’s purpose in the cells, how it affects breast cancer cell growth and how it interacts with immune cells. Using breast cancer tissue samples from IU patients, cell models and animal models, she found that breast cancer cells express more MAL2 than normal cells. She also discovered that high levels of MAL2 significantly enhanced tumor growth, while inhibiting the protein can almost completely stop tumor growth.

In Lu’s lab, he used a three-dimensional, patient-derived model called an organoid to better understand how reducing MAL2 could improve patient outcomes.

“Tumor cells can evade immune attacks; with less MAL2, the cancer cells can be recognized and killed by the immune system,” Lu said. “MAL2 is a novel target. By identifying its function in cancer cells and cancer immunology, we now know its potential as a cancer immunology target.”

Lu is co-leading a cancer immunotherapy program for triple negative breast cancer as part of the Indiana University Precision Health Initiative. Both Xinna Zhang and Chi Zhang are also involved in the initiative for developing novel breast cancer immunotherapy.

 

Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy

For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of the gut microbiome through the use of stool, or fecal, transplants may help some of these individuals respond to the immunotherapy drugs.

Researchers at NCI’s Center for Cancer Research conducted the study in collaboration with investigators from UPMC Hillman Cancer Center at the University of Pittsburgh. The findings were published in Science.

In the study, some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor did respond to the drug after receiving a transplant of fecal microbiota from a patient who had responded to the drug.

The results suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells.

“In recent years, immunotherapy drugs called PD-1 and PD-L1 inhibitors have benefited many patients with certain types of cancer, but we need new strategies to help patients whose cancers do not respond,” study co-leader Giorgio Trinchieri, chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research, said in a statement. “Our study is one of the first to demonstrate in patients that altering the composition of the gut microbiome can improve the response to immunotherapy. The data provide proof of concept that the gut microbiome can be a therapeutic target in cancer.”

Research suggests that communities of bacteria and viruses in the intestines can affect the immune system and its response to chemotherapy and immunotherapy. For example, previous studies have shown that tumor-bearing mice that do not respond to immunotherapy drugs can start to respond if they receive certain gut microorganisms from mice that responded to the drugs.

Changing the gut microbiome may reprogram the microenvironments of tumors that resist immunotherapy drugs, making them more favorable to treatment with these medicines.

To test whether fecal transplants are safe and may help patients with cancer better respond to immunotherapy, Trinchieri and his colleagues developed a small, single-arm clinical trial for patients with advanced melanoma.

The patients’ tumors had not responded to one or more rounds of treatment with the immune checkpoint inhibitors pembrolizumab (Keytruda) or nivolumab (Opdivo), which were administered alone or in combination with other drugs. Immune checkpoint inhibitors release a brake that keeps the immune system from attacking tumor cells.

In the study, the fecal transplants, which were obtained from patients with advanced melanoma who had responded to pembrolizumab, were analyzed to ensure that no infectious agents would be transmitted. After treatment with saline and other solutions, the fecal transplants were delivered to the colons of patients through colonoscopies, and each patient also received pembrolizumab.

After these treatments, six out of 15 patients who had not originally responded to pembrolizumab or nivolumab responded with either tumor reduction or long-term disease stabilization. One of these patients has exhibited an ongoing partial response after more than two years and is still being followed by researchers, while four other patients are still receiving treatment and have shown no disease progression for over a year.

The treatment was well tolerated, though some of the patients experienced minor side effects that were associated with pembrolizumab, including fatigue.

The investigators analyzed the gut microbiota of all of the patients. The six patients whose cancers had stabilized or improved showed increased numbers of bacteria that have been associated with the activation of immune cells called T cells and with responses to immune checkpoint inhibitors.

In addition, by analyzing data on proteins and metabolites in the body, the researchers observed biological changes in patients who responded to the transplant. For example, levels of immune system molecules that are associated with resistance to immunotherapy declined, and levels of biomarkers that are associated with response increased.

Based on the study findings, the researchers suggest that larger clinical trials should be conducted to confirm the results and identify biological markers that could eventually be used to select patients who are most likely to benefit from treatments that alter the gut microbiome.

The clinical trial was conducted in collaboration with Merck, which sponsors Keytruda.

 

Targeted RNA nanoparticle shows early promise as liver cancer treatment

A targeted RNA nanoparticle designed to carry a chemotherapy drug along with a therapeutic oligonucleotide against chemical efflux gene might provide an effective treatment for liver cancer, according to a study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

The study, published in the Journal of Controlled Release, shows that the RNA nanoparticles efficiently target hepatocellular carcinoma cells and are stable, safe, and effective both in laboratory and animal studies. The findings suggest that the nanoparticles could offer an effective new treatment for HCC.

The RNA nanoparticles carry paclitaxel and display molecules that target HCC cells. They also contain a microRNA that inactivates a chemical efflux pump called p-glycoprotein, which usually pumps out chemotherapeutic drugs from the liver cells, making cancer untreatable.

“Liver cells express drug exporter pumps that are used to remove chemotherapeutic drugs and detoxify the body. This renders the treatment with chemical drugs ineffective,  and contributes to drug resistance,” study leader and corresponding author Peixuan Guo, professor at Ohio State’s College of Pharmacy and the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery, said in a statement. Guo also is a member of the OSUCCC – James Translational Therapeutics Program. “This could be why liver cancer responds poorly to chemotherapy treatment.”

Earlier work by Guo and his team showed that RNA nanoparticles have rubbery or amoeba-like properties that enable them to stretch, shrink then return to their normal shape.

“We believe that this amoeba and rubber-like property enables RNA nanoparticles to slip through the poorly formed walls of tumor blood vessels and enter the tumor mass,” said Guo, who directs Ohio State’s Center for RNA Nanobiotechnology and Nanomedicine.

“This same rubbery property could allow the kidneys to filter RNA nanoparticles from the blood and excrete them in the urine, thereby eliminating them from the body swiftly,” said Guo. “This, in turn, could reduce retention of anticancer RNA nanoparticles in vital organs, lowering the drug’s toxicity.”

For this study, Guo and his colleagues constructed the RNA nanoparticles using six RNA strands that self-assembled into a globular structure. The nanoparticle served as a cargo system to deliver both Paclitaxel and microRNA (miR122) along with HCC targeting ligands. They conjugated 24 molecules of paclitaxel, along with HCC targeting molecules (a derivative of galactosamine) and one microRNA to the multivalent RNA nanoparticle. The sequence for the microRNA extends from one of the RNA strands. The final structure is about 18 nanometers in size.

The study’s key findings include:

  • RNA nanoparticles selectively bind and deliver therapeutic agents into liver cancer cells efficiently.

  • The attached miR122 effectively inhibits the liver drug-efflux pump.

  • RNA nanoparticles carrying both Paclitaxel and miR122 more effectively inhibited tumor growth compared to Paclitaxel or miR122 alone; nanoparticles without treatment groups showed no cancer-cell inhibition effects.

  • Animal studies showed that the RNA nanoparticle formulation targeted tumor cells effectively and strongly inhibited tumor growth due to the synergistic effect of Paclitaxel and miR122, without affecting healthy organs.

 

KEYNOTE-598: Keytruda + Yervoy did not improve OS, PFS in Non-Small Cell Lung Cancer

Keytruda (pembrolizumab) in combination with Yervoy (ipilimumab) did not improve overall survival or progression-free survival, and instead added toxicity compared with Keytruda as monotherapy in the phase III KEYNOTE-598 study.

The phase III study evaluates Keytruda in combination with Yervoy compared with Keytruda monotherapy as first-line treatment in metastatic non-small cell lung cancer without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (tumor proportion score [TPS] ≥50%) .

Keytruda is sponsored by Merck, and Yervoy is sponsored by Bristol Myers Squibb.

The median OS was 21.4 months for patients randomized to Keytruda in combination with Yervoy versus 21.9 months for those randomized to Keytruda monotherapy (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). Additionally, the median PFS was 8.2 months for patients in the combination arm versus 8.4 months for those in the Keytruda monotherapy arm (HR=1.06 [95% CI, 0.86-1.30]; p=0.72).

“In KEYNOTE-598, the addition of ipilimumab to Keytruda did not improve overall survival or progression-free survival, and patients who received the combination were more likely to experience serious side effects than those who received Keytruda monotherapy,” Michael Boyer, chief clinical officer and conjoint chair of thoracic oncology of Chris O’Brien Lifehouse, Camperdown, NSW, Australia, said in a statement.

These results were presented in the presidential symposium at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer on Jan. 29 and published in the Journal of Clinical Oncology.

The study was discontinued due to futility based on the recommendation of an independent data monitoring committee, which determined the benefit/risk profile of KEYTRUDA in combination with Yervoy did not support continuing the trial. The DMC also advised that patients in the study discontinue treatment with Yervoy/placebo.

KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized, double-blind, phase 3 trial designed to evaluate Keytruda in combination with Yervoy compared to Keytruda monotherapy as first-line treatment for patients with metastatic NSCLC without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (TPS ≥50%). The dual primary endpoints are OS and PFS. Secondary endpoints include objective response rate, duration of response and safety.

The study enrolled 568 patients who were randomized 1:1 to receive Keytruda (200 mg intravenously [IV] on Day 1 of each three-week cycle for up to 35 cycles) in combination with Yervoy (1 mg/kg IV on Day 1 of each six-week cycle for up to 18 cycles); or Keytruda (200 mg IV on Day 1 of each three-week cycle for up to 35 cycles) as monotherapy. Non-binding futility criteria for the study were based on restricted mean survival time (RMST), an alternative outcome measure estimated as the area under the survival curve through a fixed timepoint.

The pre-specified criteria were differences in RMST for Keytruda in combination with Yervoy and Keytruda monotherapy of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.

As of data cut-off, the median study follow-up was 20.6 months. Findings showed the median OS was 21.4 months for patients randomized to Keytruda in combination with Yervoy (n=284) versus 21.9 months for those randomized to Keytruda monotherapy (n=284) (HR=1.08 [95% CI, 0.85-1.37]; p=0.74).

The differences in RMST for Keytruda in combination with Yervoy and Keytruda monotherapy were -0.56 at the maximum observation time and -0.52 at 24 months, meeting the futility criteria for the trial and confirming the benefit/risk profile of the combination did not support continuing the study.

Additionally, the median PFS was 8.2 months for patients randomized to Keytruda in combination with Yervoy versus 8.4 months for those randomized to Keytruda monotherapy (HR=1.06 [95% CI, 0.86-1.30]; p=0.72). In both arms of the study, ORR was 45.4%; the median DOR was 16.1 months for patients randomized to Keytruda in combination with Yervoy versus 17.3 months for those randomized to Keytruda monotherapy.

Copyright (c) 2021 The Cancer Letter Inc.