Oncologists Defend CAR-T After FDA Advisory

 Last month, the FDA announced that BCMA- or CD19-directed autologous CAR T cell therapies were under review after the agency received reports of several secondary blood cancers in patients who have been treated with them. But leading oncologists say the cancers appear to be rare and the therapy is lifesaving in the context of deadly malignancies that have already outwitted chemotherapy and radiation.

“I doubt you will meet a CAR-T treating physician who will change their practice due to this warning,” said Rahul Banerjee, a physician-researcher specializing in multiple myeloma at the Fred Hutchinson Cancer Center in Seattle, Wash. He added that although CAR-T can put myeloma into a durable remission, for most patients the cancer will return sooner or later, and that’s a bigger worry. In addition, “There is something called immortal time bias,” he explained. “If you get CAR-T and you live longer, your risk of a different cancer increases.”

Biopharma companies in the CAR-T space appear unfazed for now. A spokesperson for Novartis, whose Kymriah was the first CAR T therapy ever approved in 2017, told BioSpace, “Novartis has found no causal relationship between Kymriah and secondary malignancies and remains confident in [its] favorable benefit/risk profile.” A spokesperson for Gilead Sciences offered similar reassurance: “After conducting an analysis of our data, we are not aware of any evidence to date that treatment with Yescarta or Tecartus has a causal role in the development of these malignancies of T-cell origin.” Yescarta is approved for large B-cell lymphoma and high-grade B-cell lymphoma, Tecartus for relapsed or refractory B-cell acute lymphoblastic leukemia.

“To be fair,” Banerjee said, “the FDA never said CAR T therapy caused these cancers, only that they were investigating them. It was the lay press that sometimes missed that nuance.”

The Many Causes of Secondary Cancers after CAR-T

According to Bruce Levine, a specialist in cell and gene therapies at the University of Pennsylvania’s Perelman School of Medicine, about 35,000 patients worldwide have been treated with CAR T therapies, including those in clinical trials. If there are secondary cancers, “it’s a very small percentage that happen to be induced by the therapy," he told BioSpace. 

The risk of a secondary cancer after CAR-T has long been known, said Brian Skorney, a Baird senior research analyst who coauthored a research note with fellow senior analyst Jack Allen. “Is it a surprise that an engineered aggressive treatment with a viral vector results in secondary malignancies in rare cases? It’s not a surprise at all,” Skorney told BioSpace.

CAR-T involves extracting a patient’s blood, isolating immune cells called T cells and using an engineered virus to genetically modify the cells to display cancer-targeting chimeric antigen receptors (CARs). Once infused back into the patient, the CAR T cells lock onto the malignant cells and kill them. On rare occasions, though, the engineered virus might insert the CAR code at a location in the genome that disrupts the function of a gene or activates a cancer-promoting gene. This is known as insertional mutagenesis. It is one reason the FDA demands 15 years of follow-up for every CAR-T patient.

Levine listed a number of questions that need to be answered to contextualize the rare cancers: “Are the cancers CAR positive? If so, is the CAR a passenger in what happened to be a secondary malignancy, or did it provide some assist? What was the clinical status of the patient in terms of immunosuppressive therapies, radiation, prior chemotherapy and conditioning chemotherapy, all of which increase risk of a secondary cancer?”

Allen added that it should be very easy to run a genetic test on the cancer cells to see if the CAR is present. There are two types of viral vectors used in CAR T therapy, lentiviral vectors and gamma-retroviral vectors, and genetic testing could pinpoint whether one was more frequently seen in these rare secondary cancers, he said. Both analysts hope for an updated advisory from the FDA soon with more details.

The Risk-Benefit Calculation

Until it’s clear what the risk of secondary cancer is, Banerjee said the expansion of CAR-T labeling may be slowed. “I could see this warning putting a spook in the field for smoldering cancers, pre-cancers or autoimmune diseases,” he said. “But I for one would not call for the field to pause using CAR-T in the cancer setting. For instance, if you treat a patient’s cancer earlier, when they are healthier, you may end up with a lower risk of another cancer later.”

In fact, Banerjee said, he, along with other oncologists, have been hoping the FDA will expand its approval for CAR-T in myeloma, which now requires a patient to have received four previous treatment regimens. “Those previous regimens can really be tough and challenging for patients,” he said. “We’ve been hoping the FDA will allow us to move CAR-T strategically into [an] earlier phase of treatment.”

There are hundreds of companies in the CAR-T space, Skorney told BioSpace, “but the ones that took the most pain after the announcement are [those] focusing on autoimmune disease.” On Dec. 5, William Blair hosted a virtual panel on cell therapies as part of its Innovator’s Panel. In a subsequent research note sent to BioSpace by the firm, the consensus of physicians and public and private cell therapy companies was that ”the risk/benefit of CAR T cell therapies in autoimmune patients differs from that of patients with late-stage cancer as most autoimmune patients are not terminal within the next 6 months.” For these patients, the bar may be set higher for safety, with the William Blair report suggesting that any adverse events higher than grade 2 (bothersome but not dangerous) would be of concern.

The announcement of the FDA’s investigation came days ahead of the American Society of Hematology’s annual conference, which took place in San Diego from December 9-12. The advisory was a subject of discussion, Banerjee said, “at almost all of the Friday scientific symposia that touched on CAR-T.”

The FDA also recently delayed a decision on a label expansion for Bristol Myers-Squibb and 2seventybio’s Abecma (ide-cel), which had an initial review date of Dec. 16. The drug is currently allowed as a fifth-line treatment, after four other treatment regimens have been tried, and the partners had hoped Abecma would be approved for earlier use. An advisory committee meeting on the label expansion will likely occur in the first quarter of 2024 and a large group of experts will be convened then, Allen said, adding, “we’re hoping CAR-T itself will be a topic and we can all ask questions then." 

For now, Banerjee is undeterred in their enthusiasm for CAR-T. He recalled a recent patient who had been hospitalized for a month and whose myeloma had recurred and physically grown into her kidneys—a rare occurrence for a blood cancer. This patient—like every myeloma patient—only qualified for CAR T therapy after receiving four previous treatment regimens. A month after CAR-T infusion, she was in remission.

“CAR-T works very quickly and that’s what I love about it,” he said. “The benefits are very real. It’s a game changer, a lifesaver. That’s what our patients deserve.”

https://www.biospace.com/article/oncologists-defend-car-t-after-fda-advisory-/

Chinese firms look to Malaysia for assembly of high-end chips, sources say

 A growing number of Chinese semiconductor design companies are tapping Malaysian firms to assemble a portion of their high-end chips, keen to hedge risks in case the U.S. expands sanctions on China's chip industry, sources said.

The companies are asking Malaysian chip packaging firms to assemble a type of chip known as graphics processing units (GPUs), according to three people with knowledge of the discussions.

The requests only encompass assembly - which does not contravene any U.S. restrictions - and not fabrication of the chip wafers, they said. Some contracts have already been agreed, two of the people added.

The people declined to disclose the names of the companies involved or to be identified, citing confidentiality agreements.

Seeking to limit China's access to high-end GPUs that could fuel artificial intelligence breakthroughs or power supercomputers and military applications, Washington has increasingly placed restrictions on their sales as well as on sophisticated chip-making equipment.

As those sanctions bite and an AI boom fuels demand, smaller Chinese semiconductor design firms are struggling to secure sufficient advanced packaging services at home, analysts have said.

Some of the Chinese companies are interested in advanced chip packaging services, two people said.

Advanced packaging of chips can significantly improve chip performance and is emerging as a critical technology in the semiconductor industry. This sometimes involves the construction of chiplets where chips are packaged tightly to work together as one powerful brain.

Although not subject to U.S. export restrictions, it's an area that can require sophisticated technology which the firms worry might one day be targeted for curbs on exports to China, the two people added.

Malaysia, a major hub in the semiconductor supply chain, is seen as well placed to grab further business as Chinese chip firms diversify outside of China for assembling needs.

Unisem, majority owned by China's Huatian Technology, and other Malaysian chip packaging companies have seen increased business and inquiries from Chinese clients, said one source who was briefed on the matter.

Unisem Chairman John Chia declined to comment on the company's clients but said: "Due to trade sanctions and supply chain issues, many Chinese chip design houses have come to Malaysia to establish additional sources of supply outside of China to support their business in and out of China."

Chinese chip design firms also see Malaysia as a good option because the country is perceived as being on good terms with China, is affordable, with an experienced workforce and sophisticated equipment, two of the sources said.

Asked whether accepting orders to assemble GPUs from Chinese firms could potentially provoke U.S. ire, Chia said Unisem's business dealings were "fully legitimate and compliant" and the company did not have the time to worry over "too many possibilities".

He noted that most of Unisem's customers in Malaysia were from the United States.

The U.S. Department of Commerce did not respond to requests for comment.

Other big chip packaging firms in the country include Malaysian Pacific Industries and Inari Amertron . They did not respond to Reuters requests for comment.

Chinese companies are also interested in having their chips assembled outside China as that could also make it easier to sell their products in non-Chinese markets, said one source, an investor in two Chinese chip startups.

A MAJOR HUB

Malaysia currently accounts for 13% of the global market for semiconductor packaging, assembly, and testing and is aiming to boost that to 15% by 2030.

Chinese chip firms that have announced plans to expand in Malaysia include Xfusion, a former Huawei unit, which said in September it would partner with Malaysia's NationGate to manufacture GPU servers - servers designed for data centres and which are used in AI and high-performance computing.

Shanghai-based StarFive is also building a design centre in Penang, and chip packaging and testing firm TongFu Microelectronics said last year it would expand its Malaysia facility - a venture with U.S. chipmaker AMD.

Offering an array of incentives, Malaysia has attracted multi-billion dollar chip investments. Germany's Infineon said in August it would invest 5 billion euros ($5.4 billion) to expand its power chip plant there.

U.S. chipmaker Intel announced in 2021 that it would build a $7 billion advanced chip packaging plant in Malaysia.

Chinese companies are not just choosing Malaysia. In 2021, JCET Group, the world’s third-largest chip assembly and testing company, completed an acquisition of an advanced testing facility in Singapore.

Other countries such as Vietnam and India are also seeking to expand further into chip manufacturing services, hoping to lure clients keen to minimise U.S.-Sino geopolitical risks.

https://www.marketscreener.com/quote/stock/INFINEON-TECHNOLOGIES-AG-436299/news/Chinese-firms-look-to-Malaysia-for-assembly-of-high-end-chips-sources-say-45585938/

Nobel Prize Winner Seeking to Cure Cancer With mRNA Technology

 by Naveen Athrappully via The Epoch Times (emphasis ours),

Nobel Prize winner Dr. Drew Weissman talked recently about using mRNA technology to prevent the development of cancers among vulnerable people.

Dr. Weissman suggested using mRNA vaccines to prevent cancers during his Nobel Prize lecture on Dec. 7. “The idea here is that you treat people before they develop cancer,” he said. Dr. Weissman won the Nobel Prize for medicine this year along with Dr. Katalin Karikó for developing a method to prevent the immune system from launching inflammatory attacks when lab-made mRNA is injected into the body, thus enabling the therapeutic use of the medical technology.

This allowed for the rapid development of mRNA COVID-19 vaccines. Dr. Weissman and his team at the University of Pennsylvania are now focusing on using mRNA technology to treat cancer.

A vaccine under development by the team teaches the body to identify and fight tumor cells. The vaccine is aimed at people who have a genetic mutation which raises their risk of cancer.

For instance, BRCA is a gene that contributes to breast cancer risk. Out of the more than 18 million cancers identified globally every year, around five to 10 percent stem from genetic mutations.

The Nobel Prize winner and his team investigated methods to use mRNA to trigger an immune response in the body that would kill cancer cells.

In experiments with mice, the researchers injected mRNA that taught the body to produce a protein called IL-12. This protein directs the body to produce immune cells called effector T-cells that can remove cancer.

“We know that it's five or 10 years that cancer cells first start to appear before you've got full-fledged large tumors that impair function,” Dr. Weissman said during his lecture.

“If we treat these people, maybe every 5 years, with a vaccine that only makes effector T-cells, [it] will clean out, clear away, kill all of the transformed cells and maybe completely prevent cancer from ever appearing in these patients.”

mRNA Treatments

Many pharma companies are already researching the use of mRNA for cancer therapy. This month, Moderna and Merck & Co. announced that they have begun a late-stage trial of their experimental personalized mRNA treatment for patients with a type of lung cancer.

The therapy, called v940, will be tailored for each patient individually to trigger T-cells. It will be offered in combination with the drug Keytruda. In July, the two companies kicked off a late-stage study of the combination therapy in patients with melanoma, a skin cancer.

Earlier this year, BioNTech, the company that partnered with Pfizer to make the COVID-19 mRNA vaccines, said that it had signed a deal with the UK government for personalized cancer therapies.

According to the deal, up to 10,000 patients will be enrolled in clinical trials by the end of 2030. The cancer therapies will use mRNA technology in their treatments.

In addition to cancer, mRNA technology is being investigated for use in the treatment of allergies, genetic diseases, heart attack, stroke, heart failure, neurodevelopmental disorders, HIV, malaria, and tuberculosis.

Developing mRNA to vaccinate against other diseases when the existing technology has considerable flaws brings up several safety questions.

Researchers in a landmark new study have discovered a sequence within the Pfizer mRNA COVID vaccine that produces an “unintended immune response” in the body, which experts are calling a massive “developmental and regulatory failure.”

Synthetic Messenger Ribonucleic Acid (mRNA), such as that used in Moderna and Pfizer vaccines, enables the body to create a specific spike protein mimicking SARS-CoV-2. The body reacts to the foreign protein and generates protective immunity, which theoretically neutralizes the real virus when it enters the body.

“Researchers from the Medical Research Council (MRC) Toxicology Unit have discovered that the cellular machinery that ‘reads’ mRNAs ‘slips’ when confronted with repeats of a chemical modification commonly found in mRNA therapeutics. In addition to the target protein, these slips lead to the production of ‘off-target’ proteins triggering an unintended immune response,” said a press release for the study published in Nature on Dec. 6.

Last week, Florida Surgeon General Dr. Joseph Ladapo demanded that federal health officials provide more info on the discovery of DNA fragments in Pfizer and Moderna COVID-19 vaccines “hitchhiking into human cells.”

In a letter to officials at the CDC and the U.S. Food and Drug Administration (FDA), he pointed out that the presence of Simian Virus 40 (SV40) promoter/enhancer DNA in the vaccines poses a “heightened risk of DNA integration into host cells.”

“DNA integration could theoretically impact a human’s oncogenes—the genes which can transform a healthy cell into a cancerous cell,” he warned.

There is also research showing that COVID-19 mRNA vaccines can reduce a beneficial gut bacteria called Bifidobacteria, the presence of which is associated with higher immunity against pathogens and cancer.

https://www.zerohedge.com/markets/nobel-prize-winner-seeking-cure-cancer-mrna-technology

Taiwan reports more suspected Chinese weather balloons crossing Taiwan Strait

 Two suspected Chinese weather balloons flew across the sensitive Taiwan Strait on Sunday but stayed well to the north of Taiwan, the island's defence ministry said on Monday, the second time this month Taipei has reported them nearby.

The potential for China to use balloons for spying became a global issue in February when the United States shot down what it said was a Chinese surveillance balloon, but which China said was a civilian craft that accidentally drifted astray.

Taiwan is on high alert for Chinese activities, both military and political, ahead of the Jan. 13 presidential and parliamentary election. Taipei has warned of Beijing's efforts to interfere in the ballot to get voters to pick candidates China may prefer.

Taiwan's defence ministry said the two balloons were detected at 9:03 a.m. (0103GMT) and 2:43 p.m. (0643) after crossing the strait's median 110 nautical miles (204 km)northwest of the northern Taiwanese port city of Keelung.

The balloons flew at an altitude of about 27,000 feet (3,230 metres), headed east and disappeared at 9:36 a.m. and 4:35 p.m., respectively, the ministry added.

The ministry's initial judgement is that they were weather balloons, spokesperson Sun Li-fang said.

China's defence ministry did not immediately respond to a request for comment.

The earlier balloon, which Taiwan reported crossing the Taiwan Strait on Dec. 7, was most likely also a weather platform, Taiwan's defence ministry said at the time, adding that officials had announced its detection in the interests of transparency.

https://news.yahoo.com/taiwan-detected-two-chinese-balloons-011118581.html

Cell-based therapy to destroy solid tumors

 Wistar researchers successfully tested a simple intervention that could unlock greater anti-tumor power in therapies that use T cells -- an approach known as "cell-based therapy," which uses specially designed T cells to fight cancer. Led by Dr. Hildegund C.J. Ertl -- a professor in The Wistar Institute's Vaccine & Immunotherapy Center -- the team has proven an exciting concept: that the common cholesterol drug fenofibrate can boost T cells' ability to destroy human tumors, as described in their new paper, "Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma," published in Molecular Therapy Oncolytics.

CD8+ T cells work very well in fighting liquid tumors, but for solid tumors like melanoma, the cell-based therapy approach can stall due to the physical structure of the cancer.

The T cells infiltrate the tumor, but the cancer adapts and saps the T cells' energy by hijacking the form of metabolism that the T cells use: glycolysis, which turns sugar into energy.

Without energy, the T cells first lose functions and then die, and the cancer continues to grow.

But Dr. Ertl's team has been able to circumvent this problem by forcing T cells to use a different energy source than glucose.

They used fenofibrate because, as a cholesterol-lowering compound, the drug is a PPARα agonist.

When PPARα is upregulated, cellular metabolism is switched from glycolysis to fatty acid oxidation, or FAO.

This mechanism works to improve cholesterol levels in human patients, but for Dr. Ertl's purposes, the fenofibrate-induced switch to FAO provided T cells with a form of energy that cancer couldn't exploit -- which is how Dr. Ertl proved that fenofibrate has been able to boost the killing power of T cells deployed against cancerous cell lines.

In this paper, the authors wanted to see whether this kind of cancer-killing improvement would have similar effects when deployed against not just cancer cell lines but solid human tumor fragments -- a more challenging proposition.

The group treated T cells with fenofibrate, and the hypothesis held: Dr. Ertl's team watched the T cells treated with fenofibrate survive longer and kill more cancer in preclinical models with human solid tumor masses than the T cells that didn't receive the treatment.

"Treating T cells with fenofibrate before using them as a cancer treatment flips a switch of sorts in their metabolism," said Dr. Hildegund Ertl.

"Once that switch is flipped, T cells can destroy the cancer much more effectively. And we've confirmed that this holds for larger human tumor masses."

As a result of these findings, Dr. Ertl and her team think this intervention shows great promise for future anti-tumor therapies. "Melanoma is the most dangerous form of skin cancer. Anything we can do to chip away at the cancer and destroy more of it -- even a simple pre-treatment step like this one -- can make a world of difference."

Journal Reference:

1. Mohadeseh Hasanpourghadi, Arezki Chekaoui, Sophia Kurian, Raj Kurupati, Robert Ambrose, Wynetta Giles-Davis, Amara Saha, Xu Xiaowei, Hildegund C.J. Ertl. Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma. Molecular Therapy - Oncolytics, 2023; 31: 100744 DOI: 10.1016/j.omto.2023.100744

https://www.sciencedaily.com/releases/2023/12/231213133505.htm

Risk of cell therapy for heart repair

 A type of cell that plays a crucial role in tissue repair after a heart attack may also inadvertently be why cutting-edge cell therapies cause an increased risk of rhythm disorders, according to a new study from the Universities of Surrey and Oxford. Researchers hope the findings could open up new pathways to safe regenerative treatments for people who have suffered a heart attack.

The research focused on the interactions between cells created in the lab from stem cells called Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with myofibroblasts, a type of cell that looks to repair heart tissue after a heart attack.

The study, published by Cellular and Molecular Life Sciences, found that myofibroblasts affect the electrical properties and calcium handling of hiPSC-CMs.

Myofibroblasts also altered the expression of genes responsible for vital functions of heart cells, leading to electrical instability.

Dr Patrizia Camelliti, lead author of the study from the University of Surrey, said:

"Understanding the relationship between myofibroblasts and hiPSC-CMs could be the key to developing safe regenerative treatments for those who have suffered a heart attack. Our study identified Interleukin-6 (IL-6), a molecule released by myofibroblasts involved in inflammatory responses, as a key player in this interaction. We found that blocking IL-6 signalling reduced the negative effects of myofibroblasts on heart cells.

"While this study marks a step in the right direction for understanding how cell therapies unwittingly cause heart rhythm damage, further research is needed to bring these findings into clinical practice."

Heart attacks lead to the loss of heart muscle cells and the formation of scar tissue involving cells known as myofibroblasts.

To repair this damage, scientists have been exploring the use of stem cells, such as hiPSC-CMs, to regenerate healthy heart muscles.

However, these therapies have been shown to increase the risk of heart rhythm issues, which can be life-threatening.

The research team used advanced cell culture systems to replicate the interactions between these cell types, observing the effects on heart cell function.

They cultured hiPSC-CMs with adult human cardiac myofibroblasts in three conditions to mimic cell interactions: direct contact, non-contact, and medium conditioning.

Targeting interactions between cardiac cells could provide a novel therapeutic strategy to improve the outcome of cardiac cell therapies and treat heart rhythm disorders as discussed by Dr Patrizia Camelliti in a perspective published by Science.

Journal Reference:

1. Robert D. Johnson, Ming Lei, John H. McVey, Patrizia Camelliti. Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes. Cellular and Molecular Life Sciences, 2023; 80 (9) DOI: 10.1007/s00018-023-04924-3

https://www.sciencedaily.com/releases/2023/12/231213112854.htm

With more people are using CBD products, still little research on benefits and risks

 CBD use increased 50% in the past four years, according to a new survey published Wednesday in the Journal of the American Medical Association.

About 1 in 5 survey respondents said they used CBD in the past year.

People who use cannabis are more likely to report using CBD, CBG and other hemp-derived compounds, the survey, done by NORC at the University of Chicago, showed. Also, people who live in a state where marijuana is illegal are more likely to use delta-8 THC, a mildly intoxicating sibling of delta-9 THC, which is the psychoactive compound in marijuana.

"Although there are a lot of survey studies out that show this increased use, we don't have a lot of good data on what effects any of these things have, either harmful or beneficial," said Angela Bryan, a University of Colorado-Boulder professor who has studied the public health implications of cannabis legalization for more than a decade. She was not involved in the JAMA study.

CBD and similar compounds have boomed in popularity since the 2018 farm bill legalized hemp production, and are found in lotions, tinctures, candies, vapes and more. While there is a lack of government regulation for the products, the U.S. Food and Drug Administration did approve one drug that contains CBD in 2018 to help treat two rare seizure disorders.

Surveys show people use CBD and other hemp compounds to treat everything from anxiety and sleep issues to pain. But experts say there is not enough clinical research on the compounds. The FDA warned CBD can cause liver injury and can poorly interact with certain medications.

Delta-8 THC is of particular concern, because of adverse side effects and because of how it is chemically manufactured.

Several states, including Colorado, ban or regulate delta-8 THC, though it is sold in many states due to a loophole in federal law.

"The implication in the paper, and I think it's accurate, is that if you don't have access to legal delta-9, then you're going to seek out delta-8," Bryan said. "But we know even less about delta-8 than we do about delta-9."

More information: Adrianne R. Wilson-Poe et al, Past-Year Use Prevalence of Cannabidiol, Cannabigerol, Cannabinol, and Δ8-Tetrahydrocannabinol Among US Adults, JAMA Network Open (2023). DOI: 10.1001/jamanetworkopen.2023.47373

https://medicalxpress.com/news/2023-12-people-cbd-products-benefits.html