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Interesting article from Fresenius
https://www.fiercebiotech.com/medtech/fresenius-outlines-plans-to-expand-extracorporeal-care-portfolio-to-hearts-lungs
Controlling CRS in Mice
CAR-T cell therapies that transform a patient’s own immune cells into cancer-killing weapons have been hailed as breakthroughs for treating some blood cancers. But managing cytokine release syndrome (CRS), the most common acute side effect associated with CAR-T cells, is still a challenge. A team of researchers in Germany has now found a possible solution in Bristol-Myers Squibb’s leukemia drug Sprycel.
Scientists at the University Hospital Würzburg showed that Sprycel can act quickly to put a temporary pause on CAR-T cells in mice, sparing some of the animals from the potentially fatal CRS. The findings, published in the journal Science Translational Medicine, suggest the drug could be used as an “on/off switch” for CAR-T cells, they say.
CRS is triggered by the release of inflammatory molecules from both CAR-T cells and innate immune cells. Currently available methods to rein in CRS either cannot completely control CAR-T cell function or can kill the anti-cancer effect for good.
CAR-T therapies contain CD8+ killer T cells and CD4+ helper T cells. In lab dishes, the University Hospital Würzburg researchers found that Sprycel could lock these two types of CAR-T cells in an inactive state by interfering with an enzyme called LCK, thereby preventing them from producing inflammatory molecules that cause CRS. The blockade lasted for seven days, with no signs of the effect wearing off, according to the team.
But can the off switch be reversed? The researchers carefully removed Sprycel from cell cultures and discovered that the CAR-T cells rapidly switched back on and started killing target cells. Within seven hours, CAR-T cells had regained their full power at breaking down target cells, the team reported.
The study’s senior author Michael Hudecek and colleagues compared Sprycel’s inhibitory effect with that of dexamethasone, a steroid that’s commonly used to control CAR-T cells by systemic immunosuppression. They showed that Sprycel could immediately put a complete halt to CAR-T activities, whereas dexamethasone acted more slowly and exhibited only partial inhibition.
RELATED: Redesigned CAR-T eliminates dangerous cytokine release syndrome in lymphoma trial
To verify the findings, the German team also used a mouse model of lymphoma. Giving Sprycel to a subgroup of mice soon after CAR-T infusion prevented fatal CRS in 70% of rodents, while only 25% of untreated mice survived CRS, the team found. After Sprycel was discontinued, CAR-T cells also quickly resumed their anti-lymphoma activity.
CAR-T therapies are being examined for their potential beyond blood cancer, so containing potentially life-threatening CRS will be vital. Researchers led by the University of Southern California recently used a CAR (chimeric antigen receptor) variant that they say produced lower levels of cytokines. And researchers from San Raffaele Hospital in Italy and Memorial Sloan Kettering in New York found that using the Amgen-developed rheumatoid arthritis treatment Kineret could be an effective way to control CRS.
Now Sprycel might also serve as a good emergency drug to quickly shut down CRS in patients receiving CAR-T infusions. Its rapid onset and complete but reversible control over CAR-T cells makes it an attractive option because there are multiple clinical scenarios where CRS is only transient, Hudecek’s team said in the study.
What’s more, using Sprycel at defined intervals might also serve a second function: protecting CAR-T cells becoming exhausted and ineffective. When the cells are engaged in chronic signaling, that can cause fatigue that limits their cancer-killing power. Sprycel could prevent T-cell exhaustion by giving the cells a short break, the researchers suggest.
raptorjockey - The point of my most recent posts has been to show that there
are a multitude of barriers to overcome in order for cytosorb to be used as
an adjuvant to CAR T-cell therapy. There certainly appears to be the
potential for cytosorb to play a role in this therapy but I think the
investors on this board should understand that, at least in the US, there
may be a long road ahead for this to occur. I am a long term investor in
cytosorb but try to remain realistic in my expectations.
CMS delays payment decision for CAR T-cell therapy
While the Centers for Medicare & Medicaid Services has said it plans to cover what's best known as CAR T-cell therapy for cancer patients, that determination is going to take a little longer than planned.
On Friday, CMS announced a delay in its final national coverage determination for chimeric antigen receptor (CAR) T-cell therapy, in which oncologists use a patient’s own immune system to attack a tumor.
CMS did not give a reason for the delay, simply saying in a statement: "CMS will not be issuing a final National Coverage Determination on CAR T-cell therapy for cancer today, but a decision is forthcoming."
CMS first initiated a national coverage analysis for CAR T-cell therapy for cancers last May and began considering public comments. In February, CMS posted a proposed decision memo saying it intends to allow Medicare to pay for CAR T.
The plan includes several data requirements. Hospitals and clinicians looking to offer the treatments must join a registry that tracks outcomes data for comparison with clinical trials. Clinical studies must follow similar guidelines, including tracking data for two years after the treatment.
In CAR T-cell therapy, a patient’s white blood cells are extracted and modified with a receptor that drives the cells to seek out the cancer and attack it. The ultimate goal of the therapy is to not only kill existing tumors but provide an internal line of defense against future cancers.
Groups like the the American Society for Transplantation and Cellular Therapy (ASTCT) said making a national coverage determination was "premature."
"ASTCT opposed the establishment of a National Coverage Determination (NCD) due to concerns that it would cause significant and ongoing barriers to providing current and future CAR-T therapies to beneficiaries in need of these breakthrough treatments," the group wrote in a comment submitted to CMS. "Patients who receive CAR-T have typically exhausted all other available therapies. The Society still believes that it is premature to implement a NCD because this is a rapidly evolving area of medicine. A coverage policy should not be developed until the field matures."
RELATED: How Sean Parker is working to build 'a clone army of cancer-killing assassins' for patients
America's Health Insurance Plans (AHIP) also weighed in, encouraging caution from CMS. "We agree with CMS that there is currently limited evidence for CAR-T Therapies. To date, studies have consisted of single-arm trials performed in specialty-trained hospitals with small sample sizes; we agree that a CED will allow CMS to collect additional evidence," wrote Kate Berry, AHIP's senior vice president for strategic planning.
They asked CMS to consider evaluating collecting long-term efficacy and safety data to ensure quality care and improved health outcomes through the CED, evaluating nonmedical costs associated with CAR-T and offering more clarity around who will be administering patient registries required for patients who will receive CAR-T.
However, manufacturers wrote in with support for the a coverage determination, pointing out the growing evidence supporting CAR T-cell therapy.
Among them was Kite Pharma, which manufacturers Yescarta, the first FDA-approved CAR T-cell therapy for adults with relapsed or refractory large B-cell lymphoma, which questioned whether CED was necessary.
RELATED: CMS proposes updates to hospital wage index, payments for emerging therapies
"We believe that the existing and growing body of evidence strongly supports that CAR T-cell therapy is reasonable and necessary for Medicare beneficiaries," wrote Michael Amoroso, senior vice president and head of worldwide commercial cell therapy at Kite Pharma. Kite was calling for CMS to remove the CED coverage limit that restricts treatment to patients who have relapsed or refractory cancer to allow coverage for all patients with cancer who receive CAR T therapy for any FDA approved indications or indications recommended by the National Comprehensive Cancer Network.
Celgene, which got its own CAR T-cell therapy with its $9 billion Juno Therapeutics acquisition last year, also called for expanded coverage of the immunotherapy.
"Medicare beneficiaries are disproportionately impacted by several of the cancer types currently under study for treatment with CAR T cell therapy. Therefore, CMS’s final National Coverage Determination (NCD) will be critical to ensure patient access to current and future treatment options as CAR T cell therapy continues to rapidly evolve and progress," wrote Richard Bagger, executive vice president of corporate affairs and market access for Celgene. "We are concerned that the [proposed decision memo], as currently structured, would limit CMS’s flexibility to cover future CAR T therapies that could receive FDA approval within the next two years for unique patient populations or that have different characteristics (e.g., safety, dosing) than the two products currently available to patients."
The company made recommendations to increase flexibility such as aligning patient eligibility criteria for CAR T-cell therapies with FDA-approved labeling or medically accepted indications recognized in Medicare-approved compendia and covering the therapy under the CED framework when administered at an appropriately qualified site regardless of the site’s status as a hospital.
Elimination of CRS in CAR-T Treatments
Personalized CAR-T treatments for leukemia and lymphoma have offered new hope for patients with tough-to-treat disease, but the engineered cell therapies can cause a dangerous immune reaction called cytokine release syndrome (CRS). Researchers led by the University of Southern California Norris Comprehensive Cancer Center have designed a new type of CAR-T to eliminate that side effect—and they have evidence from a small human study that they’re on the right track.
The CAR-T cell therapy tested at USC caused no serious side effects in 25 lymphoma patients who received it, the university announced today. Six of the patients went into complete remissions. The study was published in the journal Nature Medicine, and the researchers are planning a phase 2 study in a larger group of patients, according to a statement.
CRS occurs when immune cells release a stream of substances into the bloodstream that cause symptoms such as fever, rash, breathing trouble and brain swelling. Because the side effects can be life-threatening, many CAR-T recipients have to be treated on an inpatient basis.
RELATED: Stem cells combat CAR-T cytokine release in mice
Ever since the FDA approved two CAR-T therapies in 2017, Novartis’ Kymriah and Gilead’s Yescarta, oncology researchers have been experimenting with different methods for making the technology safer. Last year, Melbourne-based Cynata Therapeutics said it had developed mesenchymal stem cells that can tamp down CRS reactions. Scientists at the Fred Hutchinson Cancer Research Center have identified biomarkers that can predict CRS and are experimenting with different varieties and dosages of CAR-T cells.
The USC research focused on finding a safer CAR (chimeric antigen receptor) molecule than what’s used in the two CAR-T therapies that are FDA approved, both of which kill CD19-bearing cancer cells. They landed on a CAR variant called CD19-BBz(86), they explained in the study.
When T cells were transduced with CD19-BBz(86) in the lab, they produced lower levels of cytokines but maintained their ability to kill CD19 tumor cells, the USC-led team reported. CD19-BBz(86) CAR-T cells did not cause CRS in mice.
The researchers went on to test the cells at three different doses in the clinical trial. The six patients who achieved remissions received the highest dose, and five of them were still disease-free more than six months after receiving the CAR-T cells. Two additional patients in that arm of the trial experienced partial remissions. Some of the study participants did report mild side effects, but none required treatments for them, according to the authors.
"Toxicities are currently the biggest barrier to the use of CAR T-cell therapy,” said senior author Si-Yi Chen, M.D., Ph.D., professor at USC’s Keck School of Medicine. “My hope is that this safer version of CAR T cell therapy could someday be administered to patients in outpatient settings
Carl June on another scientific advisory board
Kiadis is set to buy CytoSen Therapeutics to expand into anti-cancer natural killer (NK) cell therapies. The all-stock transaction will give Kiadis control of a preclinical NK cell therapy and see it add CAR-T pioneer Carl June to its scientific advisory board.
Dutch biotech Kiadis has focused its efforts to date on T cell therapies, specifically a drug designed to improve outcomes in cancer patients who undergo partially matched, haploidentical hematopoietic stem cell transplants (HSCT). That drug, ATIR101, could come to market in Europe later this year and is on the road to the phase 3 data needed to win global approvals.
With ATIR101 potentially closing in on the end of clinical development, Kiadis is set to add another asset to its pipeline by acquiring CytoSen for 1.94 million shares upfront. Kiadis trades at around €10 ($11) a share.
CytoSen has spent the past few years working on NK cell technology licensed from the University of Central Florida. Using a nanoparticle processing technology, CytoSen thinks it can improve the expansion and activation of NK cells, thereby facilitating multiple high-dose infusions with potent anti-cancer effects. The goal is to augment a patient’s innate immunity to wipe out cancer cells, either as a monotherapy or in combination with T cells that dial up the adaptive immune response.
“I believe the fields of NK cells and T cells are enormously synergistic and the combination could potentially help patients with devastating diseases,” the University of Pennsylvania’s Carl June said in a statement. June, a scientific adviser to CytoSen, will join Kiadis’ scientific advisory board when the deal closes.
Stefan Ciurea and Dean Lee, co-founders of CytoSen, demonstrated the potential of NK cell therapy in proof-of-concept work performed with their colleagues at MD Anderson Cancer Center. NK cells were given in conjunction with haploidentical HSCT to 13 leukemia patients. One of the patients relapsed, resulting in a relapse rate the authors called “remarkably low.”
CytoSen set out to build on the findings by holding a pre-IND meeting with the FDA last year ahead of a planned phase 2 trial of its lead NK program, CSDT002-NK, in high-risk acute myeloid leukemia or myelodysplastic syndrome patients undergoing haploidentical HSCT.
At one point, that trial was due to get underway in the first half of this year, but Kiadis is aiming toward a 2020 start date. By then, Kiadis may have won approval for ATIR101 in Europe and could be about a year away from generating the phase 3 data it needs to support filings in the U.S. and other regions.
The CytoSen deal provides Kiadis with a fairly low-risk way to gain a backup to ATIR101 and set the stage for possible combinations of NK and T cell therapies. Kiadis will absorb the $6 million in cash held by CytoSen when it closes the deal, partly offsetting the upfront stock costs. And it will pay milestones tied to six clinical development and regulatory events using 5.82 million shares, at most.
raptorjockey-
Please see my previous post (#14364) referencing Bellicum Pharmaceuticals.
My understanding from reading the medical literature is that the use of
CAR-T therapy is far from an exact science with varying degrees of side
effects of which cytokine storm is at the extreme. Bellicum has tried to
gain better control of the process by administration of a product (rimiducid)
which to some degree controls the activation of the CAR-T cells thus elimination or reducing some of the side effects. In the very small series
outlined in the article in my previous post, there were no episodes of
cytokine storm. As progress is made in CAR-T therapy, the treatment will
most likely become more refined with better control of the process and a
reduction and/or elimination of some of the side effects. The role of
cytosorb in CAR-T therapy will depend to some degree on how well the drug
companies are able to refine the treatment and reduce the side effects.
Regarding your question as to why there seems to be a lack of interest
in cytosorb from the leaders of CAR-T research; in medicine, everything
happens slower than you anticipate.
Interesting article on CAR-T therapy from Wall Street Journal
By Charley Grant
Feb. 8, 2019 7:30 a.m. ET
A major investment by the drug industry isn’t turning out the way investors hoped.
Drug companies have spent big on chimeric antigen receptor T-cells, or CAR-T, cancer therapies. The treatment involves a process whereby a patient’s T-cells are extracted, modified and reinserted into the body to fight cancer.
The treatments are exciting from a scientific point of view and have provided significant clinical benefits to a small number of patients with severe and uncommon forms of cancer. Turning the therapy into a great business for drugmakers, however, hasn’t been smooth.
Gilead Sciences shares fell Tuesday, after the company unveiled disappointing fourth-quarter results on Monday afternoon. One reason for the negative reaction is that Gilead took an $820 million impairment charge related to research costs from its 2017 acquisition of CAR-T specialist Kite Pharma.
That wasn’t the only bad sign for that deal, for which Gilead paid $11 billion in cash. Gilead has booked only $271 million in revenue from Yescarta, the lead drug it acquired in the deal.
Gilead is hardly alone: Novartis booked $76 million in 2018 sales from a similar drug, Kymriah. Not to be outdone, Celgene spent $9 billion last January to acquire CAR-T specialist Juno Therapeutics. Juno’s drug candidates have yet to reach the market.
There are good reasons for the slow start. Cost is one reason: The drugs themselves have per-treatment list prices of $373,000 and up. That tab runs much higher once extras like hospital stays or ancillary prescription medicines are included. The drugs also can have dangerous side effects. Only a relatively small number of hospitals are certified to administer the treatment because it is complicated and labor intensive. Clinical trial results needed to expand the market to more common forms of cancer, such as solid tumors, are likely years away.
The situation is set to improve. Gilead said on a conference call this week that Yescarta sales could double in 2019 as more patient centers come online. Novartis also had an upbeat message about Kymriah’s growth prospects back in January. Drug development can evolve quickly, and it is possible that the next generation of CAR-T treatments will have much better commercial prospects.
Until evidence emerges, though, Wall Street analyst estimates seem too high. Analyst consensus calls for $1.6 billion in sales of Yescarta and $851 million in Kymriah sales by 2023. That implies 43% and 61% annual sales growth for Gilead and Novartis, respectively, over the next five years.
Pharma investors should be watching carefully. Many of the higher-profile drugs in development that excite Wall Street, such as new gene-therapy medicines, are designed to treat a fairly small number of patients with a one-time treatment. A slow start for CAR-T isn’t a great sign for the overall business model.
There are lessons for management teams as well. Growth is in short supply across the industry. The slow development of the CAR-T market shows that big drugmakers can’t necessarily solve that problem by simply opening their wallets.
First data on "controllable" CART-T adds to the knowledge of how to avert
and manage CRT. Very early limited study but significant.
Bellicum Pharma has the first data on BPX-601, its first CAR-T with a built-in activation switch to boost its effects, and says initial results show signs of biologic activity.
Data from 12 patients enrolled in a phase 1/2 dose-escalation study in PSCA-positive metastatic pancreatic cancer treated with the CAR-T showed that out of six evaluable patients, four had stabilized disease, with two seeing tumor shrinkage of at least 20%. More importantly, however, the results suggest BPX-601 is working as intended.
The PSCA-targeting therapy is designed to activate in the body after patients are dosed orally with a small-molecule drug called rimiducid. In patients who weren’t given the drug, there was only a limited expansion of the CAR-T cells and little persistence in the body. However, a single dose of rimiducid given to four patients seven days after BPX-601 caused cell numbers to expand between three- and twentyfold and persist for at least three weeks.
It’s a preliminary readout, but it suggests the activation mechanism for BPX-601 and follow-up CAR-Ts is working. Now, the big test is to see if that translate to a therapeutic advantage—Bellicum reckons that activation should enable the CAR-T to override immune inhibitory mechanisms, including the PD-1 and TGF-beta pathways.
Emboldened by the early readout, Bellicum says it is now adding additional tumor types to the trial and moving ahead with plans for repeat rimiducid dosing to extend the activation phase of treatment.
The safety profile of BPX-601 also looks clean so far, with no cases of the cytokine-release syndrome (CRS) and neurotoxicity that have been an issue with some other CAR-Ts.
The BPX-601 trial was being designed when CRS-related deaths were being reported with Juno’s now-abandoned JCAR015, and speculation that the conditioning regimen used to prepare the immune system to receive the CAR-T—and specifically a drug called fludarabine—was at fault.
For that reason, Bellicum’s trial only used cyclophosphamide to condition patients, which may not have created the best environment to allow the CAR-Ts to flourish. Now—in light of the greater knowledge of how to avert and manage CRS—it plans to add fludarabine back into the conditioning regimen.