Penn researchers find a way through the labyrinth keeping CAR-T from solid tumors – Endpoints News
Posted: December 3, 2020 at 2:56 pm
Blood vessels are supposed to act like trees, pumping in oxygen tissues need to grow and immune cells required to clear out pathogens. But in tumors, the forest can go a bit haywire. Vessels grow prodigiously and bulge and twist at abrupt points, making it difficult to even tell whats a vein and whats an artery. It starts to look less like a forest and more like a gnarled root floor. A disorganized labyrinth, one oncologist has called it.
For cancer, chaos is a virtue. That gnarled root floor insulates solid tumors from immune cells and, in recent years, has flustered drug developers best attempts at developing therapies meant to rev up the immune system and direct it toward the tumors.
Researchers at the University of Pennsylvania, however, think they may have stumbled onto a solution, a way of whipping the blood vessels back into proper shape. If it works, experts say, it could pave the way for CAR-T treatments that attack solid tumors and potentially improve the effectiveness for more traditional approaches, such as radiation and chemotherapy.
Its a really novel and potentially important approach, Patrick Wen, a neuro-oncologist at Dana-Farber who was not involved in the work, told Endpoints News. They really did good work. This is a very different way of improving immunotherapy.
Yi Fan, a radiation oncologist and neurosurgeon at Penns School of Medicine, has been working for the last few years to understand why the labyrinth appears in the first place. Researchers had previously circled in on the so-called growth factors that stimulate blood vessel formation. Attempts to block these factors, though, disappointed; Avastin, an antibody against the factor VEGF, became a blockbuster but has continually failed to improve survival on a range of malignancies.
Scientists would have to go more fundamental. In a pair of 2018 papers, Fan showed that part of the problem is a process called endothelial cell transformation. Cells lining the blood vessels around the tumor acquire stem cell-like properties that allow them to reproduce and expand rapidly, as stem cells do.
Theres a genetic reprogramming, Fan told Endpoints. Theyll become really aggressive.
But how did that reprogramming happen? If Fan could pin down the pathway, he figured he could then devise a way to block it. He started knocking out kinases the cellular engines that can drive epigenetic change, or reprogramming one by one in endothelial cells isolated from patients with an aggressive brain cancer called glioblastoma. Out of 518, 35 prevented transformation and one did so particularly well: PAK4.
Then they injected tumors into mice, some who had PAK4 and some who had the kinase genetically removed: Eighty percent of the mice who had PAK4 removed lived for 60 days, while all of the wild-type mice died within 40. Fans team also showed that T cells infiltrated the tumors more easily in the PAK4-less mice.
It was a fortuitous finding: Drug companies had developed several PAK inhibitors a decade ago, when kinase inhibitors were the flashiest thing in pharma. Many had been abandoned, but Karyopharm had recently brought a PAK4 blocker into Phase I.
To see whether drug developers could exploit this finding, Fan and his team removed T cells from mice and developed a CAR-T therapy to attack the tumors.
They gave mice three different regimens. The CAR-T therapy on its own failed to reduce tumor size, apparently unable to reach through the vessels. The Karyopharm drug also had little effect on its own. But combined, they managed to reduce tumor size by 80% after five days. They published the results in Nature Cancer this week.
It is a really eye-opening result, Fan said. I think we see something really dramatic.
That, of course, is just in mice, but Fan already has strong supporting evidence for PAK4s role in cancer. Last December, while Fan was still completing his experiment, Nature Cancer published a paper from Antoni Ribas UCLA lab suggesting that PAK4 inhibitors can help T cells infiltrate around various solid tumors. They showed that the same Karyopharm inhibitor could boost the effects of PD-1 inhibitors in mice, allowing activated T cells to better reach tumors.
That work has already translated into the clinic; weeks after it came out, Karyopharm added an arm to their Phase I study of the drug that will look at the PAK4 inhibitor in combination with the PD-1 blocker Opdivo.
Ribas said that Fans work is compelling and helps confirm the role of PAK4, but he said a CAR-T therapy would face a much longer path to the clinic. Its simply much easier to combine an approved drug with an experimental one than to devise a new CAR-T therapy, mix it with the unapproved inhibitor (and all the other things, such as bone marrow-clearing chemotherapy, CAR-T recipients receive) and then deduce what effect each is having.
It will a take a while, Ribas told Endpoints. But I hope this is right and its developed clinically.
There are also other unresolved obstacles for CAR-T in solid tumors, Wen said. Developers still struggle to find targets that wont also send the super-charged T cells after healthy tissue. And tangled blood vessels are just one of several mechanisms tumors have of defending themselves. They can, for example, turn tumor-eating immune cells into tumor-defending ones.
Still, Wen said, in the short term, the approach offered a path toward boosting the efficacy of radiation, chemotherapy and other small molecule drugs. Although Fan focused on glioblastoma, researchers agreed PAK4 likely plays the same vessel-warping role in many other solid tumors.
Theres a lot of things you could look at, he said.
In a January review, Jessica Fessler and Thomas Gajewski at the University of Chicago said Ribas paper pointed towards a path for improving PD-1 and overcoming resistance in some tumors. But they also raised questions about the Karyopharm drug, noting that it hits other proteins besides PAK4. That could mean other mechanisms are also at play and that the drug could affect other tissues in humans.
Ribas agreed that Karyopharms drug might not be the perfect molecule but said others could be on their way. He serves as a scientific advisor to Arcus, the Terry Rosen startup that is now working on developing its own PAK4 inhibitor.
If they can develop a very selective PAK4 inhibitor, he said, it may be a more direct way of testing the role of PAK4.
Tests with that drug, in turn, could help clear up a biological mystery that emerged out of Fans and Ribas papers. Although both investigators zeroed in on PAK4, each of them suggested very different mechanisms by which PAK4 kept immune cells out of the tumor. Ribas suggested it directly suppresses T cells, while Fan found it led to those transformations inside the blood vessels near the tumor.
Kinases are versatile proteins and both researchers said its possible that PAK4 is doing both. Its also possible, they said, that one is more important than the other, or simply that one of them is just wrong.
When you start with completely new biology, its hard to get it right the first time, Ribas said.
See the original post here:
Penn researchers find a way through the labyrinth keeping CAR-T from solid tumors - Endpoints News
- This Pitt program is leveling up the gene therapy workforce in Pittsburgh - University of Pittsburgh - March 12th, 2024
- Opinion | Banning Gain-of-Function Research Would Do Far More Harm Than Good - Medpage Today - March 12th, 2024
- The Biggest Challenges Facing Broader Adoption of Novel Cell and Gene Therapies - Pharmaceutical Executive - March 12th, 2024
- Research and development areas of focus - Bristol Myers Squibb - March 4th, 2024
- Overcoming the challenges of gene therapy - Drug Discovery News - March 4th, 2024
- Breakthrough Gene Therapy for LHON: Vision Restoration in Focus at Medical Conference - BNN Breaking - March 4th, 2024
- Revolutionizing Healthcare: Global Gene Therapy Market Surges to US$ 3.44 Billion by 2022 As Revealed In Ne... - WhaTech - March 4th, 2024
- Looking to the future of clinical trials: Gene therapy, precision medicine, and the ongoing quest for rare disease solutions - pharmaphorum - March 4th, 2024
- Complement system response to AAV vector gene therapy - EurekAlert - February 23rd, 2024
- 10 gene therapy companies you should know about - Labiotech.eu - February 23rd, 2024
- Fetal surgery expert Tippi MacKenzie shifts to in-utero gene therapy - STAT - February 23rd, 2024
- Rejuvenate Bio Announces Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age ... - Business Wire - February 23rd, 2024
- Combatting HIV using gene therapy - Drug Target Review - February 23rd, 2024
- Expanding the Horizons of Cell and Gene Therapy - RegMedNet - February 23rd, 2024
- Global Advanced Therapy Medicinal Products CDMO Market Analysis Report 2024-2030: : Increasing Investment and ... - Yahoo Finance UK - February 23rd, 2024
- 2023 gene therapy research STAR Grant winners announced - Pacific Biosciences - February 13th, 2024
- Lifetime Cost of DEB Gene Therapy Could Be $15-$22 Million - Medscape - February 13th, 2024
- 5 Things Youll Learn in Frederick Community Colleges New Cell and Gene Therapy Essentials Certificate ... - BioBuzz - February 13th, 2024
- Regenxbios investigational gene therapy shows promise in Hunter syndrome - PMLiVE - February 13th, 2024
- Topical Gene Therapy Effective in Treating Debilitating Eye Condition - InventUM - University of Miami - February 13th, 2024
- Bayer Says First Patient Randomized In Askbio Phase II Gene Therapy Trial - XM - February 13th, 2024
- Top 3 grants in regenerative medicine: January 2024 - RegMedNet - February 13th, 2024
- Realistic Expectations, Limitations With Gene Therapy for Parkinson Disease: Ignacio Mata, PhD - Neurology Live - February 5th, 2024
- Gene-Based Therapy May Slow Development of Life-Threatening Heart Condition - NYU Langone Health - February 5th, 2024
- After Promising Early Efficacy, Eli Lilly Eager to Study Hearing Loss Gene Therapy in More Children - precisionmedicineonline.com - February 5th, 2024
- Gene therapy hailed as medical magic wand for hereditary swelling disorder - The Guardian - February 5th, 2024
- France Approves Gene Therapy Clinical Trial to Treat Hearing Loss in Children - The Hearing Review - February 5th, 2024
- Early Trial Success for Inherited Deafness Gene-Therapy - RegMedNet - February 5th, 2024
- Can gene therapy be the key to restoring hearing loss? - Labiotech.eu - February 5th, 2024
- Jaguar Gene Therapy Announces FDA Clearance of IND to Study JAG201 in a Genetic Form of Autism Spectrum ... - Business Wire - February 5th, 2024
- FDA inspection clears Abeona's gene therapy BLA By Investing.com - Investing.com - February 5th, 2024
- Hearing Restored in Deaf Children in Gene Therapy Clinical Trial - Securities.io - February 5th, 2024
- Experimental gene therapy allows kids with inherited deafness to hear - The Associated Press - January 28th, 2024
- Children with genetic deafness have hearing restored with gene therapy: Study - ABC News - January 28th, 2024
- Positive Phase 1/2 Clinical Trial Data for an Investigational Gene Therapy for Genetic Hearing Loss to be Presented at ... - Investors | Eli Lilly and... - January 28th, 2024
- UChicago Medicine among the first in the country to offer newly approved sickle cell gene therapies - UChicago Medicine - January 28th, 2024
- Gene Therapy Allows an 11-Year-Old Boy to Hear for the First Time - The New York Times - January 28th, 2024
- Gene therapy restores hearing in children with hereditary deafness - EurekAlert - January 28th, 2024
- Experimental gene therapy helps treat kids with inherited hearing loss - CBS News - January 28th, 2024
- Children's Hospital of Philadelphia Performs First in U.S. Gene Therapy Procedure to Treat Genetic Hearing Loss - PR Newswire - January 28th, 2024
- Gene Therapy Brings Hearing to Kids With Congenital Deafness - U.S. News & World Report - January 28th, 2024
- Gene Therapy Restores Hearing in Small Trial for Kids With Hereditary Deafness - Technology Networks - January 28th, 2024
- Cell Therapies on Ice: Seven Trends in Cryopreservation To Enable Cell and Gene Therapy Research - Technology Networks - January 28th, 2024
- Gene Therapy Brings Hearing to Kids With Congenital Deafness - HealthDay - January 28th, 2024
- Gene therapies restore hearing in several kids with inherited deafness - Livescience.com - January 28th, 2024
- 11-Year-Old Boy Hears For First Time Ever Thanks To Gene Therapy Breakthrough - IFLScience - January 28th, 2024
- Innovative Gene Therapy Restores Hearing In Deaf Child, Offering Potential Cure - Study Finds - January 28th, 2024
- Sound of Success, Gene Therapy Breakthrough Grants Hearing to Deaf Children in China-Harvard Study - Hoodline - January 28th, 2024
- Perspectives in FTD Research Webinar: Gene Therapy for FTD -- What Do I Need to Know? | AFTD - AFTD - January 20th, 2024
- UK leads the way in cell and gene therapy - Research Professional News - January 20th, 2024
- Charles River's (CRL) New Launch to Boost Gene Therapy Programs - Yahoo Finance - January 20th, 2024
- UK maintains status as an attractive destination for advanced therapy clinical trials - BioPharma-Reporter.com - January 20th, 2024
- Understanding the impact of AI on the advancement of gene therapy development - pharmaphorum - January 20th, 2024
- Gene therapy TSHA-102 delivered to 1st child in REVEAL trial - Rett Syndrome News - January 20th, 2024
- AAV Vectors in Gene Therapy Market is Predicted to Observe Skyrocketed Growth During the Study Period (2019-2032 ... - PR Newswire - January 20th, 2024
- Family pins hopes on gene therapy - The Recorder and Times - January 20th, 2024
- Arbor, 4DMT partner on new gene therapies in ALS, other diseases - ALS News Today - January 11th, 2024
- The year of gene therapy? FDA's Marks calls for solutions to regulatory, manufacturing challenges - BioWorld Online - January 11th, 2024
- Gene Therapy Approvals Expected to Ramp Up in 2024 Amid Manufacturing, Cost Challenges - BioSpace - January 11th, 2024
- Turning On Gene Therapy with the pA Regulator - RegMedNet - January 11th, 2024
- Revolutionizing Healthcare: Gene Therapy Market Projected to Reach USD 46.5 billion by 2030 at a 22. - PharmiWeb.com - January 11th, 2024
- Regeneron CEO Reveals the Game-Changing Potential of Gene Therapy in Biotech! - BioTecNika - January 11th, 2024
- Bayer's AskBio checks off another early win for gene therapy platform with Parkinson's safety data - FierceBiotech - January 11th, 2024
- Are Rare Brain Diseases the Next Commercial Frontier for Gene Therapy? - MedCity News - January 3rd, 2024
- Novartis, Voyager Ink Up-to-$1.3B Expansion of Neuro Gene Therapy Collaboration - Genetic Engineering & Biotechnology News - January 3rd, 2024
- Novel switch turns genes on/off on cue, a promising step toward safer gene therapy - Phys.org - January 3rd, 2024
- Which Therapeutic Areas Experts Think Will Gain Traction In 2024 - Clinical Leader - January 3rd, 2024
- Voyager Therapeutics and Novartis Announce Major Licensing Deal in Gene Therapy Field - Medriva - January 3rd, 2024
- We Are About to Enter the Golden Age of Gene Therapy - Inverse - January 3rd, 2024
- Revolutionizing Gene Therapy: Baylor Researchers Develop RNA-Based Switch for Therapeutic Protein Control - BNN Breaking - January 3rd, 2024
- Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease - Yale Medicine - December 25th, 2023
- Top story: Family connects with researchers behind Canavan gene therapy - UMass Medical School - December 25th, 2023
- Excision Bio Seeks to Suppress HIV Replication With CRISPR Gene Therapy - AJMC.com Managed Markets Network - December 25th, 2023
- Hemgenix Gene Therapy Shows Long-Term Efficacy, Safety in Hemophilia B Patients - Managed Healthcare Executive - December 25th, 2023
- The missing piece of the puzzle - EUobserver - December 25th, 2023
- Brace yourselves for these trends in clinical research in 2024 - Labiotech.eu - December 25th, 2023
- RegMedNet's 2023 remix: top content of the year - RegMedNet - December 25th, 2023
- BU Researchers Helped Develop the First FDA-Approved Gene Therapies to Treat Sickle Cell Disease - Boston University - December 16th, 2023
- Research discovers that mice possess a natural gene therapy system - Phys.org - December 16th, 2023
- Cell- and gene-therapy hub bound for Lake Success; New York to invest up to $150 million - Newsday - December 16th, 2023