Immatics finds a multi-tumor target for adoptive T-cell therapies

 Despite the hype around adoptive T-cell therapies, it’s still a challenge to find therapeutic targets that are consistent across tumor types and aren’t expressed in healthy cells. Now, a team of scientists from the University of Pennsylvania working with immunotherapy drug development biotech Immatics has identified an antigen component that checks both of those boxes.

In a study published Wednesday in Science Translational Medicine, the researchers reported their finding of a protein that when targeted through adoptive T-cell receptor therapy slowed cancer growth in mice. The protein was highly prevalent in tumor samples from patients with 11 different types of solid tumors but was rarely present in healthy cells, making it a prime potential target for T-cell therapies. Now, Immatics plans to pursue an investigational new drug application with the FDA in hope of launching a phase I clinical trial.

The team’s goal for its research was to find antigens that were present in different tumor types and could safely be targeted in T-cell therapies without harming other cells. They started by analyzing sets of normal and tumor tissue samples with Immatics’ XPRESIDENT discovery platform, which uses mass spectrometry to examine and compare hundreds of peptides across the immunopeptidome, or the ensembles of peptides associated with human leukocyte antigens. The XPRESIDENT analysis was paired with the company’s XCUBE bioinformatics approach, using artificial intelligence to quantify peptide copy numbers in each cell. 

“We detect and quantify what’s there and what makes the difference between cancer and normal,” Toni Weinschenk, co-corresponding author and Chief Innovation Officer at Immatics, explained in an email. In other studies, immune system peptides have been analyzed through binding predictions. But with Immatics' discovery platform and bioinformatics tools at their disposal, the team could take a quantitative approach. “We don’t have to predict,” Weinschenk said.

The scientists pinned down an antigen component that was highly expressed in cancer cells from multiple types of tumors but rarely in human tissue: an epitope encoded by exon 6 of the gene collagen type VI α-3, or COL6A3, which is produced from a tumor-specific alternative splicing event that rarely happens in healthy cells. The COL6A3 protein is a component of type VI collagen, which is present in connective tissue throughout the body, but exon 6 is expressed only in the stroma cells of the tumor microenvironment.  

“Protein collagen type VI alpha-3 (COL6A3) is abundantly expressed and therefore not selective enough to be targeted by adoptive cellular therapy,” Weinschenk said. “The tumor selectivity is based on a tumor-associated splicing event, which retains the target-encoding exon 6.”

With a target in their sights, the researchers set out to develop T-cell receptors, or TCRs, that would recognize the epitope without attacking other peptides. Again using data from Immatics' discovery platform to compare reactivity between tumor and normal cells, the team developed high-affinity TCR-T cells and injected them into mice that had been grafted with human leukemia cells. The cancer growth slowed, and the mice didn’t experience serious side effects.

To Weinschenk, the results show how the company's XPRESIDENT approach can be used not only to identify potential therapeutic targets but also to develop TCRs with strong safety profiles.

Next, Immatics plans to conduct more studies on the COL6A3 epitope to support its IND application with the FDA, though the company didn’t offer a timeline. If it were to move forward with a phase I trial, the new epitope would be the ninth product in the company’s pipeline on top of its programs with Genmab, GSK and Bristol Myers Squibb.

https://www.fiercebiotech.com/research/one-protein-many-cancers-immatics-finds-multi-tumor-target-adoptive-t-cell-therapies

Florida says FDA stalling on drug importation program in suit

 It’s Florida versus the U.S. Food and Drug Administration as the state’s quest to import cheaper prescription meds from up north has veered into court this week.

Florida is suing the U.S. drug regulator for allegedly dragging its feet on a Freedom of Information Act (FOIA) request linked to a drug importation program. Florida Gov. Ron DeSantis inked legislation on the issue back in June 2019.

The so-called Canadian Prescription Drug Importation Program aims to do what it says on the tin: bring cheaper medicines from Canada to the Sunshine State.

Florida is one of a handful of states angling to draw down cheaper medicines from Canada. Other states seeking permission to buy drugs from the Great White North include Colorado, Maine, New Hampshire, New Mexico and Vermont.

Back in 2020, then-President Donald Trump blessed a rule paving the way for such imports, though the measure has been met with opposition from industry heavyweights like the Pharmaceutical Research and Manufacturers of America. 

The trade group at the time voiced “grave concerns” about the drug import plan’s potential to expose people in the U.S. to “the dangers of counterfeit or adulterated drugs,” though its own lawsuit to block the Trump-era decision has since stalled, Endpoints News points out.

For its part, the FDA says it's "working to implement a statutory pathway for the importation of certain prescription drugs from Canada." 

Florida predicts the program could save local taxpayers up to $150 million a year once fully rolled out, according to a lawsuit filed Monday in Tampa Federal Court. The plan would start by importing drugs to treat HIV and AIDS as well as diabetes, hepatitis C and mental illness, the court documents state.

Florida says it’s “ready, willing, and able to begin operating the program immediately,” pointing out that it’s “already built” a refrigerated distribution center and locked in an approved importer and distributor that's currently on retainer for $1.2 million a month.

But Florida’s ability to kick off the import scheme is “stuck in the starting blocks” because the FDA must first approve the program, for which the state claims it submitted the required proposals back in November 2020.

“In the nearly two years while Florida’s [Section 804 Importation Program] proposal has been pending, the FDA has asked for several clarifications and supplements but has provided no outward evidence of substantive progress towards approving the proposal,” the Florida lawsuit states, adding that the “FDA has also refused to provide a timeline for the approval process.”

Because the regulator has allegedly been twiddling its thumbs, Florida’s Agency for Health Care Administration secretary, Simone Marstiller, submitted a FOIA request July 6 demanding multiple records related to drug importation proposals from Florida and other states.

Problem is, the FDA has not responded according to the deadline specified in the request, the state contends in its lawsuit against the regulator.

“Plaintiffs accordingly bring this suit to compel the FDA to respond to the FOIA request and provide the requested documents,” the court filing continues.

The 2020 Trump-era rule opening the door to Canadian imports came as part of the former president’s America First Health Plan.

Drug costs are lower in Canada because the country limits how much drugmakers can charge for medicines, Kaiser Health News explained in a September 2020 report. Nevertheless, the drug industry has long rallied against import efforts on the argument it could disrupt U.S. supply chains and ease the entry of unsafe or counterfeit medications onto the market.

Plus, market watchers have pointed out that Canada is a much smaller drug market than the U.S., so it wouldn't be able to supply cheaper pharmaceuticals on a large scale. 

Florida's would-be maneuver to dodge high U.S. drug costs comes as the Biden administration makes its own play at the long-standing issue via the Inflation Reduction Act. The bill, which President Joe Biden signed into law earlier this month, includes a number of drug pricing measures, which include giving Medicare the power to bargain for certain prescription drug costs. 

The bill is also set to cap per-patient out-of-pocket costs at $2,000 per year in Medicare and is expected to shift more responsibility for expenses beyond that limit onto payers. The biopharma industry also ardently resisted the Biden administration measures.

https://www.fiercepharma.com/pharma/florida-tees-legal-showdown-fda-over-stalled-information-act-request-canada-drug-import-plan

US plots move to private market in 2023, setting up market clash between Pfizer and Moderna

 The U.S. government expects to bow out of the distribution of COVID-19 vaccines and treatments, handing the countermeasures to the commercial market. And that bodes well for marketing expert Pfizer, the company argues.

No thanks to a lack of funds authorized by Congress, the Biden administration expects it won’t be able to continue buying COVID shots and therapeutics for free distribution starting next year, Dawn O’Connell, HHS’ assistant secretary for preparedness and response, said in a blog post Tuesday.

“We have always intended to transition this work to the commercial market and have been planning for that transition for some time now,” O’Connell wrote. “Unfortunately, the timeline to make the transition has accelerated over the past six months without additional funds from Congress to support this work.”

The government-led initiative has been offering vaccines and therapeutics to healthcare providers for free. And that will for sure change in the commercial setting.

The transition may not be a bad thing for COVID product manufacturers. Once the commercial market opens up, those biopharma companies will have access to more distribution channels and the ability to utilize additional marketing tools.

Before dropping out of dispatching vaccines and treatments, the U.S. government is ending a free at-home COVID test distribution program this Friday, citing lack of funding.

In terms of vaccines, HHS has secured about 171 million doses of bivalent, omicron-targeted boosters for this fall and winter. The FDA on Wednesday just authorized updated shots from Pfizer-BioNTech and Moderna. But starting from January 2023, HHS won’t have enough federal funds to support further distributions, O’Connell said.

As for therapeutics, the federal supply of AstraZeneca’s preventative antibody Evusheld is expected to run out in early 2023, followed by Merck’s oral antiviral Lagevrio by the second quarter at the latest. The HHS expects that its stock of Pfizer’s Paxlovid will be depleted by mid-2023

Gilead’s Veklury, the first COVID treatment approved, transitioned to the commercial market in October 2020 after a short period of federal government-managed distribution. Federal distribution of several COVID antibodies by Eli Lilly, Regeneron and GSK-Vir Biotechnology have been suspended because the drugs appeared to have lost potency against omicron.

ut Eli Lilly's bebtelovimab has retained its efficacy and FDA emergency use authorization. The company has made it available for purchase in the commercial market.

Meanwhile, developers of COVID products have been bracing themselves for the expected transition. Pfizer CEO Albert Bourla and Moderna chief Stéphane Bancel have both talked up their planning to have their products in the private market.

“As we look to 2023, we are prepared for a shift to the commercial market in the U.S. for COVID boosters, where the market will be more fragmented than it was during the pandemic where the U.S. government was the sole purchaser of vaccines,” Moderna chief commercial officer Arpa Garay said during an investor call earlier this month. Moderna has talked to commercial payers, distributors and key pharmacies about the transition, she added.

As Pfizer’s Bourla sees it, Pfizer can be “even more competitive” and its commercial skills are “even better suited” in an open market than a government-contracting model, he said during an investor call in July. Even before the pandemic, Pfizer was one of the world’s leading vaccine producers thanks to its pneumococcal vaccine Prevnar, whereas Moderna is a private commercialization greenhand. 

After moving to the commercial market, Pfizer will be able to reach “a much broader set of channels that we currently do today,” Pfizer’s biopharmaceuticals chief Angela Hwang said during the call.

In terms of consumer education, Pfizer has currently limited itself to unbranded disease awareness efforts, Hwang said. But in a commercial setting, branded education could focus on Pfizer’s products, including BioNTech-partnered Comirnaty and antiviral Paxlovid.

“All of these are things that […] the commercial organization of Pfizer does really well,” Hwang said “This is our sweet spot.”

https://www.fiercepharma.com/marketing/no-more-free-covid-vaccines-us-plots-move-private-market-2023-potential-boon-pfizer

California won’t expand teen vaccines without parental OK

 California won’t allow teens age 15 and up to be vaccinated against the coronavirus without their parents’ consent.

State Sen. Scott Wiener, the bill’s author, announced Wednesday he won’t put the measure up for a vote in the state Assembly because it doesn’t have enough support to pass.

Minors age 12 to 17 in California already can receive vaccinations for hepatitis B and HPV, which prevent sexually transmitted diseases, without permission from their parents or guardians. The bill would have allowed teens 15 and older to receive any vaccine that has been approved by the U.S. Food and Drug Administration and Centers for Disease Control and Prevention, even if their parents objected.

Wiener, a Democrat from San Francisco, blamed the lack of support on “months of harassment and misinformation” by “a small but highly vocal and organized minority of anti-vaxxers.”

“The anti-vaxxers may have prevailed in this particular fight, but the broader fight for science and health continues,” he said in a statement.

A coalition of groups opposed to vaccine mandates called it a “blatant, dangerous trampling of California parents’ and guardians’ ability to protect and care for their children.”

A Voice for Choice Advocacy said minors may not know their full medical history and the potential risks. And if they don’t tell their parents that they obtained the vaccine on their own, the group said parents may not know what’s wrong if their child has an adverse reaction.

Vaccine consent ages vary across the country. Alabama allows children to consent to vaccines starting at age 14, Oregon at 15 and Rhode Island and South Carolina at 16. Cities including Philadelphia and Washington, D.C., allow children age 11 and up to consent to COVID-19 vaccines, and in San Francisco the age is 12 and older.

The teen consent bill was one several coronavirus-related bills that faced heavy opposition.

Gov. Gavin Newsom and Democratic Sen. Richard Pan both delayed until next year measures relating to school vaccinations, while Democratic Assemblymember Buffy Wicks withdrew her bill that would have forced all California businesses to require coronavirus vaccines for their employees.

Another Pan bill still moving forward would require schools create COVID-19 testing plans.

Also still under consideration are a bill by Democratic Assemblymember Evan Low that would make doctors spreading coronavirus misinformation or disinformation subject to discipline for professional misconduct, and one by Democratic Assemblymember Akilah Weber that would require health care providers, schools, child care facilities and others to disclose certain patient information to the California Department of Public Health and local health officials.

https://apnews.com/article/covid-health-san-francisco-misinformation-scott-wiener-394e55ed292f16b900343c5e6ada64f8

Georgia elementary school notifies families about case of monkeypox

 A school in Gwinnett County is reporting a case of monkeypox at one of its elementary schools.

According to a letter sent home to school families, an “individual at our school” tested positive. The school says they are taking the situation very seriously and the risk of monkeypox transmission in a school setting is “very minimal.”

The individual in question will remain off campus until cleared to return by medical professionals, according to the letter.

The letter also says that if parents were not “specifically notified with separate communication,” their child was not identified as having close contact with a known case.

The school told CBS46 that it will not share further information about the case because of privacy laws, including the gender or age of the victim. However, the health department confirmed that the person who has been infected is an adult.

Some students in the area said it is still concerning.

“Definitely a little bit, especially with the whole scare with Covid,” Sydney Spayd, a Dacula High student, said. “Just want to make sure nothing else happens.”

READ LETTER BELOW

Dear Dacula Elementary School families,

GNR Public Health notified Gwinnett County Public Schools (GCPS) today that an individual at our school has tested positive for the monkeypox virus. I want to reassure you, we are taking this situation very seriously and the risk of monkeypox transmission in a school setting is very minimal. The individual in question will remain off campus until cleared to return to school by medical officials.

In accordance with CDC guidelines, GCPS is currently contact tracing and will notify parents of any students considered to be close contacts to the affected individual. Please understand that due to HIPAA and FERPA regulations, we cannot release specific information regarding individuals.

If you are not specifically notified with separate communication, your child was not identified as having close contact with a known case, and it is highly unlikely your child was exposed.

It is very important to know that monkeypox is spread through close, direct skin-to-skin contact. While the risk of transmission is very low in a school setting, we wanted to inform you of this potential exposure. Our school facilities personnel will thoroughly clean and disinfect all affected areas of the school.

Monkeypox is a virus that causes a rash that first appears like flat spots then changes into raised bumps and then fluid-filled blisters. The person may also have a fever, headache, sore throat and or cough, and swollen lymph nodes. If you believe your student has monkeypox, please notify our school nurse and your child’s primary care physician. If your student is ill, please keep them at home until they are well and can return to school in accordance with our standard illness policy.

Again, monkeypox spreads through close, personal, skin-to-skin contact, including:

Direct contact with monkeypox rash, scabs, or fluids from the scabs of a person with monkeypox.

Less commonly, monkeypox can also be spread through touching objects, fabrics such as clothing, bedding, or towels, and surfaces that have been used by someone with monkeypox or contact with respiratory secretions.

Clear and transparent two-way communication is a core value at Dacula Elementary School. It is our commitment to keep each and every family updated about important developments at our school. We wanted to make you aware of this situation as soon as possible and assure you that we are taking all possible steps to ensure a safe and healthy learning and working environment for students and staff. You can help us by keeping your student home if he or she is feeling unwell.

If you should have additional questions regarding monkeypox, please contact your doctor or local health department for more information. You can also visit the Georgia Department of Public Health or CDC’s monkeypox webpage for additional information.

According to the CDC, three children in Georgia have been diagnosed by monkeypox. In all three cases, they contracted the virus from someone in their household.

As of Aug. 26, 1,299 cases have been reported in Georgia, placing it in the top 5 of states with highest reported number of cases.

https://www.cbs46.com/2022/08/29/gwinnett-county-elementary-school-notifies-families-about-case-monkeypox/

CDC: Handful of Swine Flu Cases Detected in Humans in Multiple States

 Five cases of human infection with flu variants normally spread only in pigs were reported to CDC in August, the agency announced in a Health Alert Network advisory on Tuesday.

Cases were detected in West Virginia, Oregon, and Ohio, and all of the individuals have since recovered.

According to the CDC, four of the infections were associated with exposure to pigs or involved individuals who had attended an agricultural fair prior to their illness. One of the individuals, however, reported no prior contact with pigs and did not attend an agricultural fair.

"No person-to-person spread associated with the five recent variant influenza virus infections has been identified," the agency stated.

Three of the cases involved the A(H3N2) variant and two involved an influenza A(H1N2) variant.The individuals suffered symptoms similar to seasonal flu, including fever, cough, pharyngitis, myalgia, and headache, and none were hospitalized, the CDC noted.

Including these new cases, 504 swine-related flu infections have been detected since the agency starting tracking the flu variants in 2005.

Medical professionals should ask patients who present with flu if they have had exposure to pigs, CDC advised: "Novel influenza A virus infections, which include those caused by variant influenza viruses, are notifiable conditions in the United States, and all confirmed cases should be reported to CDC within 24 hours."

Medical personnel are urged to take a nasopharyngeal swab or aspirate from the patient, put it in a viral transport medium, and contact the state or local health department to arrange transport and request a timely diagnosis at a state public health laboratory.

Hospitalized patients, those with severe illness, or those with a high risk of influenza complications can be treated with antiviral medication, with treatment initiation recommended within 48 hours of symptom onset, CDC said.

The agency advises that all persons at higher risk of complications of influenza avoid exposure to pigs and "swine barns" at fairs, and if avoidance is not possible, to wear a well-fitted mask that covers the nose and mouth during exposure.

The advisory noted that CDC expects that state health departments may identify more cases of infection with variant influenza viruses across the U.S., especially in late summer and fall when there are more state fairs hosting livestock, including pigs from different geographic locations.

https://www.medpagetoday.com/infectiousdisease/uritheflu/100494

Fall covid boosters: 'Likely safe,' but questions remain about efficacy

 The CDC's Advisory Committee on Immunization Practices (ACIP) will weigh in on newly authorized fall COVID boosters this week, in a manner unprecedented during the pandemic -- without data from human clinical trials.

While most experts agree that there are no safety concerns, and many support the FDA's attempt to keep up with viral variants, others have pointed out gray areas and open questions when it comes to Omicron-targeting bivalent vaccines.

That includes whether boosters with components targeting Omicron would offer a significant advantage in terms of efficacy -- particularly, protection against infection -- over boosting against the ancestral strain of the virus alone.

Regulatory Recap

To recap, the regulatory process for fall boosters started earlier this summer. On June 28, the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 19-2 to recommend the use of an Omicron-specific component in future boosters. Their review was based on human clinical trial data from a bivalent booster containing the ancestral strain and the BA.1 variant, showing sufficient levels of neutralizing antibodies after the fourth dose.

But most committee members voiced support for a bivalent vaccine that included the ancestral strain plus the BA.4/5 variants, even though data from a human clinical trial wouldn't be available before fall.

That would make the authorization process for this and possibly future COVID boosters similar to that for annual influenza vaccines, which relies on immunogenicity data from mouse studies.

Indeed, Pfizer has presented data from a mouse study, showing that BA.4/5 monovalent and bivalent boosters sufficiently raised neutralizing antibody levels against all Omicron variants.

Pfizer and Moderna are both starting human clinical trials of BA.4/5 boosters this month -- a 30-mcg dose for Pfizer and a 50-mcg dose for Moderna -- but those won't be concluded before shots likely start going into arms in the coming weeks.

The Unknowns

While proponents tout the positives of moving quickly, others have raised several concerns, including not knowing whether a BA.4/5 boost will offer better protection against infection than another boost with the ancestral strain.

Paul Offit, MD, of Children's Hospital Philadelphia, who participated in the June 28 VRBPAC meeting, told MedPage Today that the human data on BA.1 boosters were "underwhelming."

Depending on the company, he said, there was a 1.5-fold to 1.75-fold increase in neutralizing antibody titers in the group that got the bivalent vaccines, and that's "not likely to be a clinically significant difference."

That could be related to "imprinting," Offit said, which is also referred to as "original antigenic sin." The concept is that the immune system response is bolstered against the strain that a person was initially exposed to.

"You largely are hooked into that ancestral strain, so it's hard to boost in a big way with BA.4/5 vaccines," Offit said. "If I gave a monovalent BA.4/5 vaccine to a 10-year-old with no previous vaccination or natural infection, you'd see a dramatic increase in neutralizing antibodies."

Offit maintains that boosters aren't needed in healthy adult populations at all because T-cell responses are conserved and recipients are thus protected against severe disease. Boosters, he said, are beneficial in at-risk groups: older patients (above 70), those with chronic conditions, and the immunocompromised.

John Moore, PhD, professor of microbiology and immunology at Columbia University in New York City, noted that the Pfizer mouse study data actually suggested better results with a monovalent BA.4/5 booster. Thus, it's not clear why a monovalent booster isn't moving forward at this time, he said.

Moore added that recent modeling data -- albeit, a preprint, and not clinical data -- suggest there wouldn't be much of a difference in outcomes if people received a booster of the ancestral strain versus the Omicron-targeted booster.

"A great deal of time, effort, and money have now gone into making new boosters that will be little better than what we already had available in large quantities," Moore told MedPage Today in an email.

He added it would be a "mistake if the public was persuaded that the new boosters are a super strong shield against infection, and hence increased their risk and exposed themselves to more virus."

Several experts also expressed concerns that if the public perceived that the bivalent boosters were problematic because they only have animal data behind them, hesitancy could increase. That's troubling given that only about 30% of the U.S. population has taken a booster dose, they said.

Still others think FDA is on the right track. Robert "Chip" Schooley, MD, an infectious diseases expert at the University of California San Diego, told MedPage Today in an email, "I think the call was the right one."

"Coronavirus-induced immunity (whether vaccine- or infection-driven) wanes quickly and we have a large number of unboosted and under-boosted people in the population and are poised for a recrudescence of infection as people go indoors for the winter," Schooley said. "Thus, there is not time for a comparative trial with clinical efficacy endpoints before the need to roll vaccination out in anticipation of the winter surge."

He said he would have liked to see a clinical trial "embedded in the fall rollout in which people were randomized to a 'legacy' vaccine or a new one with a subset of patients being studied for immunogenicity versus a range of variants and clinical outcomes in the full cohort" -- but that he wouldn't advocate "continuing with the legacy vaccine for the next 6 months, which is what would be required to do a properly controlled clinical trial."

He concluded that COVID vaccines are "likely headed toward where flu vaccines have gone."

That certainly seems to be a foregone conclusion, as Biden administration officials have already touted the value of Omicron-targeted bivalent boosters. White House COVID-19 Response Coordinator Ashish Jha, MD, MPH, called it the "first major upgrade of the vaccines ... in the last two and a half years."

CDC Director Rochelle Walensky, MD, MPH, told the podcast Conversations on Health Care that bivalent boosters "shouldn't impact safety at all."

If the country waits for human data, she said, "we would be using what I would consider to be a potentially outdated vaccine. ... It's best to use a vaccine that's tailored to the variant we have right now."

https://www.medpagetoday.com/special-reports/exclusives/100482