UCLA opens CAR T-cell trial focused on the most common types of lymphoma, leukemia – The Cancer Letter Publications

publication date: Oct. 18, 2019

The UCLA Jonsson Comprehensine Cancer Center has launched a CAR T-cell immunotherapy trialthat will attack cancer cells by simultaneously recognizing two targetsCD19 and CD20that 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 studiesled byYvonne 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.

Chens team designed the CARs based on the molecular understanding of the CARs 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, were quite optimistic that the bispecific CAR can achieve therapeutic improvement over the single-input CD19 CAR thats currently available, said Chen, who is also the co-director of the Jonsson Cancer Centers 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-Hodgkins 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 inThe 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 hereto 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 pathologists 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 thecorrect 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 theaccuracy of thediagnosis, which is imperative to helpguide patients to the most effective treatments, said Elmore, whois 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 studys 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.

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UCLA opens CAR T-cell trial focused on the most common types of lymphoma, leukemia - The Cancer Letter Publications

Immunotherapy: using the body’s own defences to heal – Raconteur

Immunotherapy for cancer treatment made headlines when clinical trials showed that over half of patients with late-stage melanoma given a combination of these innovative drugs survived for five years. A decade ago only one in twenty survived that long.

Professor James Larkin, consultant medical oncologist specialising in melanoma and kidney cancer at Londons Royal Marsden NHS Foundation Trust, led the trial. He explains that in 52 per cent of patients who received a combination of two immunotherapy drugs, ipilimumab and nivolumab, tumours shrank.

Immunotherapy research has attracted huge investment from pharmaceutical companies and academic institutions in the last five to ten years, but we need more understanding of how it works. Numerous trials are underway and immunotherapy will continue to be a major area of research, he says.

The same combination of drugs can also be used against non-small-cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma.

Professor Larkin says: I expect the five-year survival rate of kidney cancer patients given this combination to be greater than that of patients before these treatments became available.

Immunotherapy cancer treatments began in the UK in 2003, when the drug rituximab was licensed for use in B-cell non-Hodgkin lymphoma, a cancer of the lymphatic system. But now CAR T-cell therapy, which uses the bodys own immune system to recognise and attach to cancer cells, has made a leap forward.

This has meant exciting developments in treating aggressive advanced B-cell non-Hodgkin lymphoma, says Dr Adam Gibb, clinical research fellow in lymphoma at The Christie NHS Foundation Trust, Manchester, and honorary member of the Institute of Cancer Sciences.

CAR T-cell therapy causes the lymphoma to shrink in about two thirds of cases and in a third of patients the cancer has not progressed five years later. They are effectively cured, says Dr Gibb. But more work is needed if we are to save more than one in three lives.

A new drug, which secured official US backing last year and has now gained National Institute for Health and Care Excellence approval for suitable lymphoma patients in some parts of the UK, is polatuzumab vedotin, consisting of an antibody joined to a chemotherapy drug. It is a targeted agent that kills cancer cells from the inside, explains Dr Gibb. It can put patients into remission when there are few treatment options left.

Immunotherapy drug combinations are showing good results in tackling some kinds of advanced cancers, but what about early-stage cancers? Professor Paul Lorigan, medical oncologist specialising in melanoma at The Christie, explains: Initially these combinations were evaluated in people with advanced cancers particularly responsive to immunotherapy, such as melanoma, kidney and lung cancer, but because immunotherapy works better where there is only a small amount of cancer, it is being evaluated in earlier-stage disease and is already used in the NHS to treat earlier-stage melanoma after surgery.

We can see that in patients with early-stage melanoma, adding immunotherapy to surgery to remove the tumour and lymph glands reduces the risk of recurrence by 40 to 50 per cent.

A trial to establish when this surgery-immunotherapy combination can be most effective starts soon. Using it on all early-stage patients risks delivering unnecessary, toxic and expensive treatment, says Professor Lorigan. The trial will test the use of a very sensitive blood biomarker to detect if the cancer is recurring and these patients will be treated straightaway.

Vaccines are showing huge promise, used in combination with other forms of immunotherapy. There is exciting work underway on bespoke vaccines created using cells picked up from the patients own tumour. Early-stage trials are underway now in using this for treating melanoma and lung cancer.

Meanwhile, research has begun into the potential benefits of combining radiation therapy with immunotherapy for cancer treatment.

Also known as biologic therapy, immunotherapy uses the body's immune system to fight cancer. Cancer cells suppress the immune system, so immunotherapy aims to re-empower it, allowing immune cells to find and kill cancer cells. Types of treatment include:

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Immunotherapy: using the body's own defences to heal - Raconteur

CAR-T at a crossroad as industry looks to allogeneic – Bioprocess Insider – BioProcess Insider

As cell therapies move through the clinic towards commercialization, respondents to a KNect365 industry survey are beginning to look to allogeneic or off-the-shelf products as the next big thing.

Almost 200 people contributed to the Cell Therapy Analytics Report from KNect365, revealing their current position within the burgeoning cell and gene therapy space and offering up their thoughts and predictions for the future.

The majority worked within companies developing oncology products, and the largest group 41% said they are specifically developing chimeric antigen receptor (CAR) T-cell therapies. This developmental divulgence reflects the regulatory successes of Novartis Kymriah (tisagenlecleucel) and Kite/Gileads Yescarta (axicabtagene ciloleucel), both of which shook the drug world when approved in 2017.

Image: iStock/megatronservizi

Both Kymriah and Yescarta are made using a patients own cells, which are genetically engineered and then reinserted into the patient. These autologous products require intricate manufacturing processes and a complex logistics network, leading to a very high cost of production and, naturally, a very large price tag. The two therapies have been listed at$373,000 and $475,000, respectively.

When asked where the next big success and/or approval will lie in the cell and gene therapy industry, 47% ticked the gene therapy box. This may be slightly misleading as several gene therapies have already been commercialized, the latest being AveXis/Novartis Zolgensma (onasemnogene abeparvovec) priced at $2.1 million, and while we are still in the early days of the industry.

A quarter checked Solid Tumor treatment, which makes more sense as the CAR-Ts available and about to breakthrough are all focusing blood cancers.

But more interesting is the written responses, with several stating allogeneic immunotherapies will be the next big thing in cell therapies.

Much talk has been on reducing the cost of goods for CAR-T therapies using technologies around automation and analytic, but the prospect of an allogeneic or off-the-shelf CAR-T would alter the COGS concern with cell therapies. Large batch manufacturing will play into economies of scale, and with technologies available and well-established in the antibody industry, allogeneic therapies could recalibrate the sector back to a COGS model more appealing to healthcare providers and patients.

Companies have begun to focus on allogeneic CAR-Ts; Gilead/Kite has expressed its intentions to submit an Investigational New Drug (IND) request for an off-the-shelf product before the end of the year. And Allogene, with Pfizer backing, has already begun constructing a manufacturing facility for its allogeneic pipeline.

Download the full report here.

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CAR-T at a crossroad as industry looks to allogeneic - Bioprocess Insider - BioProcess Insider

Sanofi investing in gene therapy as R&D focus turns toward rare disease – BioPharma Dive

CAMBRIDGE, Mass. Sanofi is accelerating nascent efforts in gene therapy, aiming to use its expertise in vaccines to catch up in a competitive field that's well ahead of the French pharma.

The company has prioritized gene therapy programs amid a broader effort to boost internal R&D speed and impact, said John Reed, Sanofi's head of research and development, in a Wednesday interview at Sanofi's Cambridge office.

"When I joined, I saw that we were dabbling in gene therapy and decided that we need to get more serious about gene therapy if we are going to continue to be impactful in that space," said Reed, who came over to Sanofi from Roche last July.

In particular, the company is retrofitting one of its vaccine facilities near Lyon, France, to produce GMP-grade adeno-associated viral vectors, or AAVs. Reed said he expects the plant to be operational in about a year.

The new R&D chief is steering the company away from areas for which it's historically been known, including, most notably, cardiovascular disease and diabetes. Sanofi is largely exiting cardiovascular R&D and is cutting spending in half on diabetes R&D, Reed said.

While vaccines make up a comparatively smaller portion of Sanofi's revenues, Reed noted the company's decades-long expertise in producing inactivated viruses could translate well to gene therapy. Reed was recently in Lyon to discuss the budget and headcount requirements for the change, he said.

"We have an opportunity to really leverage those competencies around vaccines for the gene therapy area," Reed said. "We are looking at how we can use that as a competitive advantage to be players in that space."

Several of Sanofi's pharma peers have bet heavily on gene therapy, investing in manufacturing and snapping up biotech leaders through multi-billion dollar acquisitions, such as by Novartis for AveXis and Roche for Spark Therapeutics.

Smaller companies like BioMarin Pharmaceutical, meanwhile, hold sizable leads in therapeutic areas that Sanofi hopes to play a larger role in, like hemophilia.

Reed acknowledged an acquisition "could be an accelerator" in establishing Sanofi's presence in cell and gene therapy.

"We flirt with those things all the time," he said, when asked about his openness to a deal like those for AveXis and Spark. "It's a bit challenging to point your finger at any one gene therapy company and say that solves all our problems."

"It's been really tough to pull the trigger on something like that," he added. "In the interim, we've been establishing the capabilities more internally."

How much it would be willing to pay, or afford, is another question. Under former CEO Olivier Brandicourt, the company last year targeted roughly 20 billion euros in acquisitions, a budget largely consumed by deals for Bioverativ and Ablynx in the blood disease space.

The company's first AAV-delivered gene therapy recently entered the clinic for a form of a rare eye disease called Leber congenital amaurosis, Reed added.

Two gene-edited cell therapies are in Phase 1/2 testing via a collaboration with Sangamo Therapeutics. Other programs remain preclinical as the group works on establishing GMP manufacturing capabilities.

All of this is taking place against a backdrop of change for Sanofi research and development teams.

Reed is working to narrow the company's focus to advance only first- or potentially best-in-class therapies, a bar that led Sanofi to cut several dozen programs from its pipeline earlier this year.

Reed has also restructured employee's incentives, taking away bonuses for starting projects and replacing them with an emphasis on starting first-in-human studies, a milestone Sanofi usually reaches slower than industry leaders.

"I don't want to reward people for starting projects, I want to reward them for finishing projects," he said. "We have too many projects."

Part of that's involved reducing bureaucracy and streamlining decision-making, moving from 33 committees that interact with R&D teams to three. Reed's given decision-making authority to team leaders for each molecule, calling them CEOs of their drug candidate.

Even before Reed came on board, productivity had begun to improve from a nadir in 2014, when Sanofi's entire organization produced only two clinical candidates that year. Now, Sanofi is delivering about six per year and, with the 2018 acquisitions of Bioverativ and Ablynx, should reach eight or nine per year.

Still, of the last 10 drugs Sanofi has won approvals for, only one was an internal project, Reed said. For the company's next 10 assets, Reed expects six or seven to have been internally developed.

As Reed re-focuses, Sanofi has exited or restructured partnerships this year with Regeneron, Alnylam Pharmaceuticals and Lexicon Pharmaceuticals.

Paring down the pipeline and restructuring deals also speaks to Sanofi's R&D budget, which the company expects to keep flat for the next few years. The pharma spends about half what companies with larger revenues like Pfizer, Novartis and Roche do.

Reed says the ultimate goal is to bring about 12 programs into clinical development each year, and growing internal R&D to the point where it's responsible for the majority of those candidates progressing.

"With the resources we have, that would be industry competitive," he added.

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Sanofi investing in gene therapy as R&D focus turns toward rare disease - BioPharma Dive