publication date: Oct. 18, 2019
UCLA opens CAR T-cell trial focused on the most common types of lymphoma, leukemia
The UCLA Jonsson Comprehensine Cancer Center has launched a CAR T-cell immunotherapy trial that will attack cancer cells by simultaneously recognizing two targets—CD19 and CD20—that are expressed on B-cell lymphoma and leukemia.
By launching a bilateral attack instead of using the conventional single-target approach, researchers are hoping to minimize resistance and increase the life expectancy for people diagnosed with these cancers.
“One of the reasons CAR T cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19, which is what the CAR T cells are engineered to target,” Sarah Larson, a health sciences clinical instructor in hematology/oncology at UCLA Health and the principal investigator on the trial, said in a statement “One way to keep the CAR T cells working is to have more than one antigen to target. So, by using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape, one of the common mechanisms of resistance.”
Up to two-thirds of the patients who experience relapse after being treated with the FDA-approved CD19 CAR T-cell therapy develop tumors that have lost CD19 expression. UCLA researchers are identifying and testing new strategies like this one so many more patients can benefit from the therapy.
In preclinical studies led by Yvonne Chen, an associate professor of microbiology, immunology, and molecular genetics at UCLA and the sponsor of the trial, the team was able to show that by simultaneously attacking two targets, the engineered T cells developed in her lab could achieve a much more robust defense compared to conventional, single-target CAR T cells against tumors in mice.
Chen’s team designed the CARs based on the molecular understanding of the CAR’s architecture, the antigen structure and the CAR/antigen binding interaction to achieve optimal T cell function. This design helps the T cells have dual-antigen recognition to help prevent antigen escape.
“Based on these results, we’re quite optimistic that the bispecific CAR can achieve therapeutic improvement over the single-input CD19 CAR that’s currently available,” said Chen, who is also the co-director of the Jonsson Cancer Center’s Tumor Immunology Program and a member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
This first-in-humans study will evaluate the therapy in patients with non-Hodgkin’s B-cell lymphoma or chronic lymphocytic leukemia that has come back or has not responded to treatment. The goal is to determine a safe therapeutic dose.
Patients enrolled in the trial will have their white blood cells (T cells) collected intravenously then reengineered in the laboratory so the T cells can produce tumor-specific receptors (CARs), which allow the T cells to recognize and attack the CD19 and CD20 proteins on the surface of tumor cells. The new “smarter and stronger” T cells are then infused back into the patient and primed to recognize and kill cancer cells.
The trial is currently only offered at UCLA.
Results from STELLAR trial in MPM published in The Lancet Oncology
Novocure said the results from the STELLAR trial were published in The Lancet Oncology.
The STELLAR trial was a prospective, single-arm trial including 80 patients that studied the use of Tumor Treating Fields, delivered via the NovoTTF-100L System, in combination with pemetrexed plus cisplatin/carboplatin as a first-line treatment for patients with unresectable, locally advanced or metastatic malignant pleural mesothelioma.
Data showed a median overall survival of 18.2 months (95 percent CI, 12.1 months-25.8 months) for patients treated with NovoTTF-100L and pemetrexed plus cisplatin or carboplatin. One- and two-year survival rates were 62.2 percent (95 percent CI, 50.3 percent-72.0 percent) and 41.9 percent (95 percent CI, 28.0 percent-55.2 percent), respectively. No serious systemic adverse events were considered to be related to the use of NovoTTF-100L. The most common mild to moderate adverse event was skin irritation beneath the transducer arrays.
“The STELLAR trial demonstrated encouraging overall survival results with no increase in systemic toxicity observed in MPM patients treated with Tumor Treating Fields and standard chemotherapy,” Giovanni Luca Ceresoli, head of pulmonary oncology at the Humanitas Gavazzeni Hospital in Bergamo, Italy, and principal investigator in the STELLAR trial, said in a statement. “The median overall survival of 18.2 months is impressive given that MPM is a tumor with a dismal prognosis and few effective therapeutic options.”
Median progression free survival was 7.6 months (95 percent CI, 6.7 percent-8.6 percent) for patients treated with NovoTTF-100L and pemetrexed plus cisplatin or carboplatin. There was a 97 percent disease control rate in patients with at least one follow-up CT scan performed (n=72). 40 percent of patients had a partial response, 57 percent had stable disease and 3 percent had progressive disease.
IASLC invites comments on “Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens Following Neoadjuvant Therapy”
The International Association for the Study of Lung Cancer announced an open comment period for the “IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens Following Neoadjuvant Therapy” paper.
The paper has been made available here to provide an opportunity for public review of new draft recommendations. The open comment period runs from Oct. 14 to Nov. 7.
With the recent growing number of neoadjuvant therapy clinical trials for non-small cell lung cancer, there is a great need for standardization of specimen processing since major pathologic response has consistently been shown to be an important prognostic indicator.
The purpose of the paper is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic complete response including major pathologic response and pathologic complete response following neoadjuvant therapy.
“Currently there is no established guidance on how to process and evaluate resected lung cancer specimens following neoadjuvant therapy in the setting of clinical trials and clinical practice,” Giorgio Scagliotti, past president of the IASLC and co-author of the paper, said in a statement. “There is also a lack of precise definitions on the degree of pathologic response, including MPR or pCR.”
IASLC is making an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestions for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.
The recommendations were developed by the IASLC Pathology Committee in collaboration with an international multidisciplinary group of experts in medical oncology, thoracic surgery and radiology.
”We are crossing an exciting period of preclinical and clinical research around thoracic oncology. Targeted therapies and immunotherapy have greatly improved survival expectations in advanced disease and we believe they can equally generate benefit in the systemic therapy of earlier stages of the disease,” Scagliotti said in a statement. “Our initiative aims to use rigorous experimental conditions to analyze tissue specimens, collected in the context of already performed or ongoing neoadjuvant studies with targeted therapies and immunotherapy, to generate a diagnostic algorithm to be used in all subsequent studies in order to accelerate the scientific information about the clinical benefit produced by the neoadjuvant approach.”
Expert second opinion improves reliability of melanoma diagnoses
Getting a reliable diagnosis of melanoma can be a significant challenge for pathologists. The diagnosis relies on a pathologist’s visual assessment of biopsy material on microscopic slides, which can often be subjective.
Of all pathology fields, analyzing biopsies for skin lesions and cancers has one of the highest rates of diagnostic errors, which can affect millions of people each year.
Now, a study led by UCLA researchers, has found that obtaining a second opinion from pathologists who are board certified or have fellowship training in dermatopathology can help improve the accuracy and reliability of diagnosing melanoma, one of the deadliest and most aggressive forms of skin cancer.
“A diagnosis is the building block on which all other medical treatment is based,” Joann Elmore, a professor of medicine at the David Geffen School of Medicine at UCLA and researcher at the UCLA Jonsson Comprehensive Cancer Center, said in a statement. “All patients deserve an accurate diagnosis. Unfortunately the evaluation and diagnosis of skin biopsy specimens is challenging with a lot of variability among physicians.”
In the study, led by Elmore and colleagues, the value of a second opinion by general pathologists and dermatopathologists were evaluated to see if it helped improve the correct diagnostic classification.
To evaluate the impact of obtaining second opinions, the team used samples from the Melanoma Pathology Study, which comprises of 240 skin biopsy lesion samples. Among the 187 pathologists who examined the cases, 113 were general pathologists and 74 were dermatopathologists.
The team studied misclassification rates, which is how often the diagnoses of practicing US pathologists disagreed with a consensus reference diagnosis of three pathologists who had extensive experience in evaluating melanocytic lesions. The team found that the misclassification of these lesions yielded the lowest rates when first, second and third reviewers were sub-specialty trained dermatopathologists. Misclassification was the highest when reviewers were all general pathologists who lacked the subspecialty training.
“Our results show having a second opinion by an expert with subspecialty training provides value in improving the accuracy of the diagnosis, which is imperative to help guide patients to the most effective treatments,” said Elmore, who is also the director of the UCLA National Clinician Scholars Program.
Elmore is now studying the potential impact of computer machine learning as a tool to improve diagnostic accuracy. She is partnering with computer scientists who specialize in computer visualization of complex image information, as well as leading pathologists around the globe to develop an artificial intelligence (AI)-based diagnostic system.
Michael Piepkorn of the University of Washington School of Medicine is the study’s first author. Raymond Barnhill of the Institut Curie is the co-senior author.
The study was published in JAMA Network Open and supported by NCI.