From The Editor | June 7, 2021

GMP CAR T Manufacturing: The Poseida Approach

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By Matthew Pillar, Editor, BioProcess Online

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Promising clinical momentum and a recent IPO are fueling Poseida Therapeutics’ unique approach to manufacturing safe, accessible, and affordable allogeneic CAR T-cell therapies. CEO Eric Ostertag, M.D., Ph.D., shares the company’s differentiating factors.

Dr. Eric Ostertag had built the foundation of what promised to be a storied academic career in Philadelphia. He earned his Ph.D. in molecular biology and M.D. degrees there at the University of Pennsylvania, with the distinction of being the first graduate of UPenn’s Gene Therapy program. That was followed by a clinical pathology residency at the Hospital of the University of Pennsylvania, where he then moved on to a transfusion medicine fellowship. He was well on his way down the research career path he’d always envisioned.

But it was during his clinical pathology residency that dissatisfaction, that nagging motivator of so many career pivots, began to creep in.

“I felt strongly that the work I was doing in gene delivery technology had commercial applications that could be out licensed, and I was frustrated that there was no active attempt to do so,” Dr. Ostertag tells me. That frustration led him to hatch a plan. He’d take his case directly to the tech transfer office, where he’d pitch a DIY proposal to spin up a company.

As presented, the idea wasn’t well-received. “They said sure, maybe, but who would run it?” he recalls. The answer seemed obvious to Dr. Ostertag. “I told them I’d run it in the short-term, until a CEO was recruited.” The response was quick. There are a hundred people with way more experience than you who want to start companies out of UPenn technology, they told him.

Undeterred, Dr. Ostertag pressed the issue. “I talked their ears off until they agreed to license the DNA non-viral transposon technology. I wrote some grants, secured some funding, and there was no one to run it but me.” Transposagen Biopharmaceuticals (now Hera Biolabs) was born.

Challenging Times For Gene Therapy

Eric Ostertag, M.D., Ph.D., CEO, Poseida Therapeutics
Eric Ostertag, M.D., Ph.D., CEO, Poseida Therapeutics
Dr. Ostertag’s foray into industry began around 2003, during early and difficult days for gene therapies. Jesse Gelsinger, the 18-year-old clinical trial patient who died from an immune response triggered by the viral vector gene therapy he received, was still fresh on the nascent industry’s mind. Funding was hard to come by.

Ahead of its time, Dr. Ostertag’s fledgling company kept the lights on by developing and selling gene editing kits, animal models, and reagent cell lines. But as its non-viral gene engineering technology advanced and the industry rebounded, two distinct companies took shape—one focused on the reagent business and one focused on the human potential of gene therapies.

“It was the treatment of Emma Whitehead with CAR-T that changed everything,” recalls Dr. Ostertag. Emma was diagnosed with acute lymphoblastic leukemia at the age of five. That’s normally a highly treatable form of leukemia, but Emma was prone to relapse and her condition developed resistance to standard treatments. In 2012 at seven years old, she was given a short time to live before becoming the first pediatric patient in the world to receive CAR T-cell therapy. Today, she’s a nine-years-cancer-free teenager.

“Emma’s story renewed hope in gene editing and gene delivery technologies. It revived Big Pharma’s interest in pursuing allogeneic CAR T-cell therapies. More specifically, it renewed their interest in sophisticated gene editing and non-viral transposon technology. We were one of only a few companies that had it.” Transposagen’s gene editing technology caught the eye of J&J’s Janssen, which inked a discovery and development deal with the company. On the heels of that deal, Dr. Ostertag spun out a company focused on the human therapeutic potential of Transposagen’s gene editing and gene delivery technology, dubbed it Poseida Therapeutics, and took the helm as CEO.  

On The Path To Fully Allogeneic CAR T-Cell Therapy

“We made the decision to start with CAR T while also further advancing our in vivo liver directed gene therapies, particularly by developing a fully biodegradable nanoparticle technology,” says Dr. Ostertag. “Five years ago, allogeneic CAR T was aspirational. I believe the key to developing successful allogeneic CAR T-cell therapies is to get the experience with autologous CAR T-cell therapies,” he says.  

When then-Transposagen signed the discovery and development deal with J&J, Dr. Ostertag gained access to some of J&J’s binders through a separate license, enabling his company to immediately set to work on the development of two autologous candidates that are currently in the clinic: P-BCMA-101 for relapsed/refractory multiple myeloma and P-PSMA-101, a solid tumor target for castrate resistant metastatic prostate cancer.

This year, Poseida is planning INDs for two fully allogeneic CAR T-cell therapies: P-BCMA-ALLO1 (the allogeneic version of the relapsed/refractory multiple myeloma candidate) and P-MUC1C-ALLO1, a “pan solid tumor target” which the company believes can address most epithelial-derived cancers, including triple negative breast, ovarian, pancreatic, colorectal, mesothelioma, and non-small cell lung cancer.

Differentiation In CAR T-Cell Production

At the heart of Poseida’s therapeutic approach is its proprietary piggyBac® DNA Delivery System. Dr. Ostertag says the system can deliver more extensive genetic cargo into cells than earlier-generation gene delivery platforms, also resulting in more stable cell integration and long-term expression than classic AAV approaches, for example, where expression fades as cells divide and expand. “In animal models, that’s enabled us to achieve single treatment cures that correct for the life of the animal.” Those results, he says, give the company hope that its approach will be particularly effective in delivering long-term, or even lifetime results for patients, including pediatric patients whose rapidly dividing livers preclude effective long-term treatments from standard, non-integrating gene therapies.

Dr. Ostertag also points out several differentiators to Poseida’s development and manufacturing approaches. Its autologous CAR-T therapies in the clinic use non-antibody-based binders targeting either prostate-specific membrane antigen (PSMA) or B cell maturation antigen (BCMA) and non-viral DNA transposon technology for transgene delivery. This non-viral approach, he says, not only results in faster and more cost-efficient GMP production but also enables a transgene cargo capacity that’s significantly larger than that offered by typical lentivirus and gamma retrovirus approaches to CAR T.

“A larger cargo capacity allows us to add in safety switches that are kinetically favorable. It allows us to add on a selection gene that gives us 100% CAR-positive cells at the end of manufacturing,” he says. Most importantly, but not as obvious, because piggyBac preferentially transposes stem cell memory T-cells (Tscm), it allows Poseida to create a fully allogeneic product with between 60% and 80% of these desirable and oftentimes rare cells, which are multipotent progenitors that self-renew and replenish more differentiated subsets of T cells. “We’ve found that this desirable Tscm cell type, which is your true T-stem cell, gives rise to all the other T-cells in your body. It works like a pro drug. It engrafts in bone marrow and lymph nodes, and then makes wave after wave of effector cells, which are the killers, or drug.” That effect, he says, is derived from the company’s piggyBac DNA transposon technology in combination with Cas-CLOVER, the gene editing technology it invented to make certain genes invisible to the immune system, and its yield-increasing Booster molecule, which enables production of hundreds of doses from a single manufacturing run but without affecting the stemness of the final product.

 

There’s a very strong correlation between the percentage of Tscm in the final product and best clinical responses, and Dr. Ostertag says this cell type can endure naturally for decades or even a lifetime, resulting in a favorable duration of response.  Furthermore, the Tscm cells may be the answer to reducing the toxicity that has plagued other CAR-T products. “We’re seeing a potentially best-in-class safety profile and much lower cytokine release syndrome (CRS) than competitive approaches. We’ve never had a patient go to the ICU due to CRS or neurotoxicity in our P-BCMA-101 clinical trial, which lends itself to fully-outpatient dosing.”

With these advantages, Dr. Ostertag believes Poseida is turning the corner on the challenges associated with CAR T-cell therapies’ inadequacies against solid tumors. In May 2021, the company released data on one of the most impressive responses ever seen against a solid tumor by a CAR product in a patient with prostate cancer – a >96% decline in PSA and a 70% reduction in standard uptake value in PSMA PET imaging of target lesions at four weeks post CAR T treatment.

Taking The CAR T-Cell Therapy Accessibility Challenge Head-On

While CAR T-cell therapies have demonstrated success in oncology compared to standard-of-care therapeutics, toxicity concerns remain. Solving those concerns is central to bringing CAR T within reach of the patient population. “Historically, administration of these projects has required a tertiary care academic medical center with an ICU, which would be reserved in anticipation that a patient might suffer a toxicity or CRS event. That's the exact opposite of accessibility,” says Dr. Ostertag. “We think a high percentage of stemness is key to solving that accessibility problem. Fully-outpatient dosing must be the goal, and that’s what we’re doing in our clinical trials.”

Dosing and cost are also obstacles that need to be overcome. “If you're only making one dose per patient, which is the case in autologous approaches, it’s a very expensive drug. Likewise, if you're making 10 allogeneic doses from a single manufacturing run, you’re still not truly reducing the cost of the drug by a factor of 10,” says Dr. Ostertag. “If you need to dose more cells per infusion, or you need dose more often, you have a less cost-effective product. That’s why stemness is such an important part of the equation, even in the allogeneic context.” Production of hundreds of doses per run, he says, drops the cost of manufacturing to the same range as monoclonal antibody, bi-specific T-cell engager, and CAR NK-cell therapies.

Well-Funded For Clinical Progress

Dr. Ostertag took Poseida public in July 2020 in the wake of an April 2019 $150 million series C financing round led by Novartis and a subsequent $110 million series D the month prior to its IPO. “In a little under 18 months we executed a crossover round and went into an IPO, all during the pandemic,” says Dr. Ostertag. “We were one of the first companies to do a completely virtual road show, and ultimately an IPO, with an incredibly efficient and entirely virtual approach. I don’t think that approach is going to change, even as the pandemic ends,” he says.

With approximately $335 million raised via its Series D and IPO, Poseida remained well-capitalized with $310 million in the bank at the outset of 2021. That money is earmarked for the progression of the clinical-stage autologous and pre-clinical allogeneic programs covered here, as well as liver-directed Ornithine Transcarbamylase (OTC) deficiency and dual CAR programs slated for 2022.

Learn more at www.poseida.com.