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Accelerating CAR T cell therapy: Lipid nanoparticles speed up manufacturing

For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague…

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For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague Professor at Penn Medicine, and approved by the Food and Drug Administration (FDA) in 2017, CAR T cell therapy mobilizes patients’ own immune systems to fight lymphoma and leukemia, among other cancers.

Credit: Ann Metzloff

For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague Professor at Penn Medicine, and approved by the Food and Drug Administration (FDA) in 2017, CAR T cell therapy mobilizes patients’ own immune systems to fight lymphoma and leukemia, among other cancers.

However, the process for manufacturing CAR T cells themselves is time-consuming and costly, requiring multiple steps across days. The state of the art involves extracting patients’ T cells, then activating them with tiny magnetic beads, before giving the T cells genetic instructions to make chimeric antigen receptors (CARs), the specialized receptors that help T cells eliminate cancer cells.

Now, Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.

In a new paper in Advanced Materials, Michael J. Mitchell, Associate Professor in Bioengineering, describes the creation of “activating lipid nanoparticles” (aLNPs), which can activate T cells and deliver the genetic instructions for CARs in a single step, greatly simplifying  the CAR T cell manufacturing process. “We wanted to combine these two extremely promising areas of research,” says Ann Metzloff, a doctoral student and NSF Graduate Research Fellow in the Mitchell lab and the paper’s lead author. “How could we apply lipid nanoparticles to CAR T cell therapy?”

In some ways, T cells function like a military reserve unit: in times of health, they remain inactive, but when they detect pathogens, they mobilize, rapidly expanding their numbers before turning to face the threat. Cancer poses a unique challenge to this defense strategy. Since cancer cells are the body’s own, T cells don’t automatically treat cancer as dangerous, hence the need to first “activate” T cells and deliver cancer-detecting CARs in CAR T cell therapy.

Until now, the most efficient means of activating T cells has been to extract them from a patient’s bloodstream and then mix those cells with magnetic beads attached to specific antibodies — molecules that provoke an immune response. “The beads are expensive,” says Metzloff. “They also need to be removed with a magnet before you can clinically administer the T cells. However, in doing so, you actually lose a lot of the T cells, too.”

Made primarily of lipids, the same water-repellent molecules that constitute household cooking fats like butter and olive oil, lipid nanoparticles have proven tremendously effective at delivering delicate molecular payloads. Their capsule-like shape can enclose and protect mRNA, which provides instructions for cells to manufacture proteins. Due to the widespread use of the COVID-19 vaccines, says Metzloff, “The safety and efficacy of lipid nanoparticles has been shown in billions of people around the world.”

To incorporate LNPs into the production of CAR T cells, Metzloff and Mitchell wondered if it might be possible to attach the activating antibodies used on the magnetic beads directly to the surface of the LNPs. Employing LNPs this way, they thought, might make it possible to eliminate the need for activating beads in the production process altogether. “This is novel,” says Metzloff, “because we’re using lipid nanoparticles not just to deliver mRNA encoding CARs, but also to initiate an advantageous activation state.”

Over the course of two years, Metzloff carefully optimized the design of the aLNPs. One of the primary challenges was to find the right ratio of one antibody to another. “There were a lot of choices to make,” Metzloff recalls, “since this hadn’t been done before.”

By attaching the antibodies directly to LNPs, the researchers were able to reduce the number of steps involved in the process of manufacturing CAR T cells from three to one, and to halve the time required, from 48 hours to just 24 hours. “This will hopefully have a transformative effect on the process for manufacturing CAR T cells,” says Mitchell. “It currently takes so much time to make them, and thus they are not accessible to many patients around the world who need them.”

CAR T cells manufactured using aLNPs have yet to be tested in humans, but in mouse models, CAR T cells created using the process described in the paper had a significant effect on leukemia, reducing the size of tumors, thereby demonstrating the feasibility of the technology.

Metzloff also sees additional potential for aLNPs. “I think aLNPs could be explored more broadly as a platform to deliver other cargoes to T cells,” she says. “We demonstrated in this paper one specific clinical application, but lipid nanoparticles can be used to encapsulate lots of different things: proteins, different types of mRNA. The aLNPs have broad potential utility for T cell cancer therapy as a whole, beyond this one mRNA CAR T cell application that we’ve shown here.”

This study was conducted at the University of Pennsylvania School of Engineering and Applied Science and is supported by the U.S. National Institutes of Health Director’s New Innovator Award (DP2 TR002776), a U.S. National Science Foundation CAREER Award (CBET-2145491), an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET), and a Burroughs Wellcome Fund Career Award at the Scientific Interface. Further support for this paper and the researchers involved came from the Emerson Collective, U.S. National Science Foundation Graduate Research Fellowships, a U.S. National Institutes of Health Ruth L. Kirschstein National Research Service Award (F31CA260922), the National Institute of Dental and Craniofacial Research of the US National Institutes of Health (T90DE030854), the University of Pennsylvania Fontaine Fellowship, the Norman and Selma Kron Research Fellowship, and the Robert Wood Johnson Foundation Health Policy Research Scholars Program. The researchers thank the Human Immunology Core at the University of Pennsylvania (RRID: SCR_022380) for assistance with primary human T cell procurement. The HIC is supported in part by NIH P30 AI045008 and P30 CA016520.

Additional co-authors include Marshall S. Padilla, Ningqiang Gong, Margaret M. Billingsley, Xuexiang Han, David Mai, Christian G. Figueroa-Espada, Ajay S. Thatte, Rebecca M. Haley, Alvin J. Mukalel and Alex G. Hamilton of Penn Engineering; Maria Merolle of Penn Vet; and Mohamad-Gabriel Alameh, Neil C. Sheppard, Carl June and Drew Weissman of the Perelman School of Medicine.

Journal

Advanced Materials

DOI

10.1002/adm

Method of Research

Experimental study

Subject of Research

Cells

Article Title

Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy

Article Publication Date

28-Feb-2024

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A detailed look at manufacturing, and an update on frieght

  – by New Deal democratAs I wrote on Monday, the big question for this year is whether the recessionary effects of the Fed rate hikes have just been…

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March 27, 2024

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 - by New Deal democrat


As I wrote on Monday, the big question for this year is whether the recessionary effects of the Fed rate hikes have just been delayed, or whether, because the rate hikes have stopped, so has the headwind they normally produce. Watching manufacturing and construction, especially housing construction, is what I expect to supply the answer.


On Monday I focused on housing construction and sales. Since there’s no big economic news today, let’s take a more detailed look at manufacturing.

There are three manufacturing metrics that are “official” components of the index of Leading Economic Indicators: the ISM manufacturing new orders subindex, average weekly hours of manufacturing workers, and capital goods new orders. Note that since manufacturing makes up less of the US economy than it did in the 20th century, it takes a steeper downturn in these components to be consistent with a recession than it used to.

Let’s start with the ISM manufacturing index and its new orders component, which were last updated at the beginning of this month:



These are in a definite uptrend, although neither has definitively broken above the dividing line of 50 which separates expansion from contraction.

Next, let’s compare capital goods new orders, which were reported yesterday for February (dark blue), with industrial production (red), a premier coincident indicator, and also manufacturing employment from the payrolls survey (gold), all YoY for easier comparison. First, here’s the historical look:



Note that capital goods orders are very noisy (one reason I typically don’t highlight them), and did not turn negative in advance of the Great Recession. Nevertheless, they generally do turn in advance of industrial production, which typically turns in advance of manufacturing employment.

A similar dynamic has existed since the pandemic:



YoY gains in new capital goods orders decelerated first, followed by industrial production, followed last by manufacturing employment. The two first metrics are generally flat YoY, and manufacturing employment is only slightly positive.

Now let’s compare the average manufacturing workweek (black) with capital goods orders, both again YoY and first historically:



The average manufacturing workweek is even more leading than capital goods orders, turning first, but is even more noisy, and over-sensitive to the downside. That is, sharp declines in manufacturing hours always happen before recessions, but a downturn in hours frequently does not presage a recession at all.

Here’s the post-pandemic look at these two metrics:



Hours turned negative first, and if anything are getting “less bad” in recent months, while capital goods new orders, as already indicated, are essentially flat YoY.

Put the data together, and you get a relatively mild manufacturing recession in 2023, which appears to be recovering this year, as the ISM new orders index and the manufacturing workweek are trending higher (if not positive yet), while capital goods orders and production are flat. Manufacturing employment growth -the least leading metric - appears still to be decelerating. 

Before I conclude, let’s take a brief updated look at transportation. Remember, the theory is that everything that is produced must be shipped to market. So to confirm a trend, both should be moving in the same direction.

Here is the Freight Transportation Index through January (dark blue), the noisier and more negatively biased Cass Transportation Index (light blue), compared with heavy weight truck sales which has been an excellent leading indicator (red):



In February, preliminarily there was a steep drop in excess of -3.5% in the Freight Transportation Index, but it has not been updated at FRED, possibly because at least one component (air freight) was withheld pending further seasonal adjustments.

There was a steep drop off in all of these metrics late last year following the Yellow Freight bankruptcy. The Cass Index and truck sales may be showing the beginning of a recovery from that, although the data is too noisy to say anything definitive.

One final note: we’ll bet a detailed updated look at the spending side of construction and production via the personal spending report this Friday.

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Argentinians Buy Bitcoin to Combat Inflation, Pass Friendly Legislation

Argentina’s plummeting economy has seen citizens turn to Bitcoin as a store of value. The legislature passes friendly laws as the pro-Bitcoin president…

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March 26, 2024

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The below is an excerpt from a recent edition of Bitcoin Magazine Pro, Bitcoin Magazine's premium markets newsletter. To be among the first to receive these insights and other on-chain bitcoin market analysis straight to your inbox, subscribe now.

As the Argentine economy is racked by record inflation, its people are turning to Bitcoin as a way to protect their economic security.

The Argentine Republic is currently experiencing the worst inflation rates in the world. The nation’s economy has experienced low levels of inflation, somewhere around 25%, for decades; yet the pandemic sharpened a downward trend to devastating effect. The inflation rate hit 70% in 2022 and reached 100% the following February, but 2023 proved to be an absolutely murderous year for Argentina's economy. Inflation rates crossed the 200% point around the time that Bitcoin-friendly president Javier Milei first took office in December, and the rate currently sits at a mind-boggling 274%. With figures like this, ordinary citizens’ wages and life savings have evaporated practically overnight, and people are looking towards more radical solutions to get their lives on track.

Source

In a particularly encouraging development, ordinary citizens are turning to Bitcoin in record numbers for its classic use-case as a store of value. Already a nation with a high rate of Bitcoin acceptance, Argentina has doubled down on the decentralized currency as the most popular local exchange reports 20-month highs in trading volume. Lemon Cash, the exchange in question, claimed that Bitcoin transactions in the first full week of March 2024 were more than double the average rate throughout 2023. Belo, another prominent exchange based in the country, reported year-to-year increases that were closer to tenfold. A particularly interesting wrinkle in the development is that Bitcoin is not only replacing dollars, but also dollar-backed stablecoins which saw trading volumes decrease by 60-70%. Belo’s CEO Manuel Beaudroit stated that “The user decides to buy Bitcoin when they see the news that the currency is going up, while stablecoin is more pragmatic and many times used for transactional purposes, as a vehicle to make payments abroad”.

Ironically, Bloomberg claims, some of President Milei’s economic positions have actually influenced the switch from the dollar to Bitcoin, but through some unexpected and indirect means. The radical libertarian has begun his administration with a series of broad-reaching reforms to try and control the situation, reducing spending and attempting to dismantle or privatize a variety of state-owned businesses. A particular goal of his administration to date has been to build a budget surplus for the federal government, for a variety of reasons: using these funds more deliberately, reaching targets based on agreements with the International Monetary Fund (IMF) and of course beginning a positive trend in Argentina’s economic statistics. A component of this surplus policy has been to build a similar reserve of American greenbacks, reducing their circulation within the country. The exchange rate of pesos to dollars took a serious hit, and the once-popular store of value became less attractive than the skyrocketing Bitcoin.

Reports from Chainalysis put some hard numbers onto these general trends: Argentina leads all of Latin America in transaction volume, and is second place overall in terms of grassroots adoption. Representatives from Lemon Cash estimated in this report that the number of Argentinians using Bitcoin or other digital currencies is around 5M, out of a population of 45M! Such impressive figures are not merely the result of a brief period of economic misfortune, but should instead be considered as a sort of tipping point: Bitcoin acceptance has been quietly growing for years, and now the crisis is providing the jump for it to become a fully mainstream fiat alternative. The rate of growth has been so prodigious that an unexpected “cousin” of the industry has even been developing, with crypto-related scam and phishing activity increasing fivefold. Clearly, the market is full of people new to Bitcoin’s chaotic ecosystem.

Relevant to the rise of unsavory activity targeting new Bitcoin users, Argentina is beginning to pass some new regulations over the industry. The Senate unanimously passed a new law in March, opening up a new set of standards that virtual asset service providers must adhere to. The standards are generally related to various consumer protection and anti-fraud precautions, with the country’s main securities agency set to enforce these new standards. The existing Bitcoin community has reacted to these new laws with consternation, fearing that this legislation will lead to market consolidation. Large operations, after all, would have the resources to comply with these new requirements immediately, while smaller startups may find themselves swamped. Still, legislators are also working on a series of tax exemptions for digital asset holders, that may hopefully help smooth over some of this animosity.

Curiously absent from these proceedings, however, is President Milei. The man espoused some pro-Bitcoin views on the campaign trail, and has a general economic philosophy that aligns with some of Bitcoin’s core fundamentals, but nevertheless he has held little public presence in many of Bitcoin’s developments. Even the incidental rise of Bitcoin fueled by his own policies have not led him to make public statements on the situation. Still, Milei has had his hands full from a far-reaching series of economic reforms and austerity policies, balancing the confidence of global markets with a concerning rise in poverty across several metrics. Milei has managed to slow the ballooning inflation somewhat, but at great cost: reduced government spending is pushing more citizens over the brink. As Reuters reported, the crisis is far from over, with sales, activity and production all on a downward slope.

In other words, it seems likely that Milei personally has Bitcoin on the back burner, as he has a much greater priority in getting the economy under control and tempering the possibility of social unrest. His general popularity is holding up despite these adversities, but a contentious issue like bitcoinization may simply be a battle he is unwilling to start. Once things calm down, we may look forward to his endorsement of Bitcoin once again, but nothing is truly certain. Still, despite his lack of direct Bitcoin-friendly initiatives, the legislature is still making positive moves in its own right. It seems very unlikely that Argentina will turn actively hostile to Bitcoin in the face of this inflation, such as with Nigeria’s crackdown amidst a lagging currency.

Ultimately, the future of Bitcoin in Argentina is up to the Bitcoiners themselves. Economic crisis has presented the community with record highs in adoption, and Bitcoin is well past a household name. Will this trend continue as the economy recovers? Will a fledgling community of Bitcoin-related businesses and developers end up transformed into a dynamic and profitable industry? There are too many variables to say for certain. Nevertheless, Bitcoin is a chaotic market that was itself founded in the wake of the United States’ own economic woes of the 2008 collapse. The worldwide community has displayed an innovative and enterprising spirit that can lead to success in even the most marginal situations. Bitcoin has been on the rise globally, in other words, and there’s no reason to doubt that it won’t keep rising in Argentina too. 

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Long Volatility Trade May Be A Widow-Maker No More

Long Volatility Trade May Be A Widow-Maker No More

Authored by Simon White, Bloomberg macro strategist,

An unusual combination of divergences…

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March 26, 2024

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Long Volatility Trade May Be A Widow-Maker No More

Authored by Simon White, Bloomberg macro strategist,

An unusual combination of divergences in the stock-market volatility space suggests the VIX is at elevated risk of pricing higher, and this may even happen with rising rather than falling equity prices. Volatility of volatility is near 10-year lows making call options on the VIX cheap.

Buying the VIX is the quintessential widow-maker trade. It is rare for the gauge to rise, with most of such instances over the last 20 years episodic and occurring when the market was falling. Most of the time, the market rises and volatility falls - there is an entire sub-industry devoted to exploiting and perpetuating this, which has swollen further in size in recent years with the boom in zero-days-to-expiry (0DTE) trading.

Not only is the VIX near its post-pandemic lows, it has also never been more out of step with cross-asset volatility – FX, fixed-income and credit (which is saying something as FX and credit vol are themselves near historic lows).

Markets are interlinked: rates impact stock valuations, high-yield credit sits just above equity in the capital structure, and so on. The question is how long can equity volatility remain the relative outlier?

There’s always a risk of becoming the next widow, but there are enough factors in play to suggest a heightened risk of a rise in the VIX.

Three trends suggest that a turning point in equity volatility is near:

  1. Divergence between the VIX and skew structure;

  2. Implied and realized correlation nearing their effective lower bound; and

  3. Stresses in state-by-state US unemployment.

The market has become increasingly bullish in recent months, especially so after making new highs. That’s led to leveraged market chasing – call buying – and reduced hedging activity, i.e. less put buying. The rally chasing spurred some truly epic moves in the call skew of certain sectors. The metals and mining and staples sectors saw the biggest rises in their call skews, with both hitting series highs.

However, since 2020, it’s the relationship between call and put skew that’s tracked the VIX almost perfectly, with the index typically falling when call skew is outpacing put skew. In other words, when there is more leveraged activity in calls relative to puts, the VIX tends to be repressed (the VIX is a weighted-average of implied volatility in the S&P across all strikes).

Now, though, put skew is outperforming call skew. As the chart above shows, that typically coincides with a rising VIX.

At the same time, the realized and implied correlation of the S&P is very depressed. Realized correlation is close to going below 10%, a level it rarely breaches, and when it does it is typically followed by a sharp move higher. Moreover, implied correlation - so called as it is implied from the Markowitz portfolio model - has never been lower.

Correlation is being driven lower by the dominance of the largest stocks and by dispersion selling. The latter involves selling volatility on the index versus buying vol on individual stocks. As the Magnificent Seven - or whatever your favored cohort of AI-related stocks is - drive higher, the dispersion selling has the effect of pinning the index. The biggest stocks go up, while the rest are impaired by how much they can move, pushing correlation down.

In theory, index correlation could go negative, but it has never happened. The reason is that stocks are not completely random and are driven by common macro-based factors, such as interest rates. Correlation is thus so low today that it can only really go one way, and when it does, history shows the move is likely to be abrupt. Something has to give.

It’s not only the market sounding a warning about stock-market vol, but the economy too. A fairly reliable indication of rising equity volatility has been when we see a number of US states experiencing stress in their employment markets at the same time.

The chart below shows the percentage of US states whose unemployment rate is higher over the past year. As we can see, while increases in equity vol don’t always coincide with rising state unemployment, almost all the spikes higher in the percentage of states experiencing worsening unemployment coincide with episodes of higher VIX.

Today is - so far, along with the mid 1990s - an outlier, with more than half of US states seeing rising unemployment while the VIX remains near its lows.

There is a proviso here. The household survey, from which the unemployment rate is derived, may be under-reporting employment growth due to underestimating immigration. A recent Brookings paper suggests that the household survey is using too low an estimate for the civilian population, which could well explain its divergence from the establishment survey (payrolls). It might also bias state unemployment rates too high if estimates of the size of the workforce are too low.

Nonetheless, this measure bears close scrutiny, especially in confluence with the endogenous market-based signs of higher equity vol mentioned above.

Being long volatility is rarely comfortable. Given the structure of the market, the path of least resistance is down. This also means the volatility curve is typically steep – as it is today – meaning an investor wears negative carry to hold the position. One way to mitigate this is through call options on the VIX. These are relatively cheap, with the VVIX – the vol of vol – near 10-year lows.

The reflex is to expect higher equity vol to come with lower stock prices. But the two had a positive correlation for much of the second half of the 1990s. The current backdrop of still-supportive liquidity, a non-recessionary economy and investor call buying could lead to a situation of rising volatility and higher equity prices. That might make long volatility trades a less likely money-losing proposition.

Tyler Durden Tue, 03/26/2024 - 10:15

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