Cell therapy: A University medical legacy enters a new era

Nearly two centuries ago, German scientists identified the cell as the basic unit of life.  Cells are life-giving through reproduction yet also life-destroying, as in cancer.  Today cells can be lifesaving as well -- as therapeutic agents, as “living drugs.” David Camp, Molly Nash, and Emily Whitehead are proof.

In 1968, University pediatrician, immunologist, and pathologist Robert Good, his assistant Richard Gatti and their colleagues carried out the first successful bone-marrow transplant that did not involve identical twins.  Eight-year-old Doreen Camp donated her marrow to her five-month-old brother David, who was suffering from severe combined immunodeficiency and not expected to live.  In 2000, University pediatrician John Wagner led a team that successfully transplanted umbilical cord blood from her newborn brother Adam to  six-year-old Molly Nash who was suffering from Fanconi anemia and not expected to live.   

Doreen Camp and Adam Nash’s healthy blood-forming stem cells reconstituted David and Molly’s diseased marrow. Both cases required an HLA tissue match to ensure that the transplanted cells could replace the diseased cells and not be rejected by the recipient’s immune system.  In the case of Molly Nash, her brother Adam was selected as an embryo during in vitro fertilization (IVF) to ensure an HLA match [See the U of M story “Almost Two Decades Later, Doctor Reflects on Using Embryo Selection to Save Young Girl’s Life.”] 

But could the field of cell therapy advance beyond donated and HLA matched blood-forming stem cells that reconstitute bone marrow in a patient?  In 2012, University of Pennsylvania immunologist and oncologist Carl June led a team that pioneered a cellular engineering therapy called CAR-T (chimeric antigen receptor T cells) to put seven-year-old Emily Whitehead’s twice-relapsed acute lymphoblastic leukemia into remission.   Today, she is cancer free and considered cured, the most celebrated example of how far immunotherapy has advanced. The Emily Whitehead Foundation was created in her name in 2015 to support CAR-T cell therapy for her fellow pediatric patients.

MCT steps to the fore in cell therapy

The U.S. Food & Drug Administration (FDA) has approved nearly 50 gene and cell therapy products since 2010 including seven involving CAR-T cells.  All have had to meet strict regulatory requirements because cellular manufacturing is much more complicated than the production of small chemical molecules that make up the lion’s share of drug formularies.  Cells have some 10 trillion molecules and are difficult to standardize, purify, and process.

No one knows that better than LMP professor David McKenna, medical director of the University’s Molecular and Cellular Therapeutics (MCT) facility on the St. Paul campus.  MCT offers current Good Manufacturing Practices (cGMP) that are FDA compliant.  It bills itself as a facility focused on “full-service development and manufacturing of cell- and tissue-based products, monoclonal antibodies and other therapeutic proteins, as well as active pharmaceutical ingredients, for use in Phase I or Phase II clinical trials.” It is a fulcrum for cell therapy translational science.  Although the facility was constructed in the 1980s to manufacture the immunosuppressive agent anti-lymphocyte immunoglobulin (ALG) derived from horses, McKenna said it has undergone a number of renovations and currently features several state-of-the-art clean rooms.  “It’s an older building for cGMP but we’ve kept the standards high,” he said.

High cGMP standards are reflected in MCT’s protocol for retrieving, processing, and manufacturing cells for CAR-T clinical trials.  Last year, for example, McKenna, LMP associate professor Andrew Johnson, and LMP then-resident Teddy Mamo and their colleagues published a protocol designed to standardize patient peripheral blood collection (apheresis) for FDA-approved CAR-T cell products.  Earlier this year, McKenna, Mamo, and Thane Kubik, a 2025 LMP cell therapy fellow, published “Manufacturing and clinical applications of non-CAR-T

immune effector cells” such as natural killer cells (NK cells), a type of white blood cell that can kill infected cells and tumor cells.  NK cells constitute a research field in which Jeffrey Miller, a professor of medicine and MCT associate medical director, is perhaps the country’s foremost authority. 

McKenna described an upcoming University collaboration with the University of Oslo and Sweden’s Karolinska Institute titled "A clinical phase I program targeting hematological malignancies with adaptive NK cells."   Patients with high-risk myelodysplastic syndrome, acute myeloid leukemia, and multiple myeloma will be treated at collaborating hospitals in a team-based effort “to bring new insights in NK cell biology to the clinic,” according to the Oslo University’s Karl-Johan Malmberg who is leading the Scandinavian team.

“It’s a long-distance collaboration,” McKenna said. “They’ll be treating patients there, we’ll be treating patients here.  Each institution will be manufacturing their own cells using the same approach, coordinating the protocol and the manufacturing.  Ours went through the FDA, theirs through the European regulatory authorities.  It’s in the process of being approved for an early-stage trial.”

A gene-editing breakthrough in TIL therapy

Immunologists are finding T cell subsets that could well point the way to the future of cell therapy for cancer and other diseases.  Perhaps the most promising is the tumor infiltrating lymphocyte (TIL), and once again MCT is pioneering protocols for TIL manufacture. TILs are T cells taken from the patient’s tumor tissue, expanded in the laboratory, and reinfused into the patient, greatly enhancing the patient’s immune response to the malignancy because these T cells can identify specific tumor cell-surface antigens. 

CAR-T cell therapy has proven quite effective against blood cancers but not so much solid tumors.  A different approach was needed.  Killer T cells that have infiltrated the tumor develop a tumor recognition advantage.  The FDA granted accelerated approval to the first TIL therapy product in 2024 for adults with metastatic melanoma.

McKenna was a member of a team led by professor of medicine Emil Lou and including pediatrics professor Branden Moriarity and associate professor Beau Webber that took TIL therapy to an unprecedented level by being first to use the CRISPR-Cas 9 gene editing system to knock out a key immune system regulatory gene called CISH, spurring T cell antitumor activity.  As reported in The Lancet a year ago, the “first-in-human single center, phase 1 trial” using TILs absent CISH involved patients with treatment-resistant metastatic colorectal cancer.  The authors wrote that they had developed “a clinical-scale, cGMP-compliant manufacturing process for CRISPR-Cas9-mediated CISH knockout in primary human TILs.” 

A commentary accompanying the paper noted:  “From a translational perspective, the results from this first-in-human clinical trial have important implications, because they underline the feasibility of using CRISPR-Cas9-engineered TILs in adoptive cell therapy for solid tumours.” Compared with the potentially serious side effects associated with CAR-T cell therapy, “CRISPR-Cas9-TIL therapy offers a safer and more biologically tailored alternative, which could emerge as an innovative immunotherapy for patients with otherwise treatment-resistant solid tumours.”

One of the 12 patients successfully treated in the study entered complete remission and remains disease free, a remarkable finding in that metastatic colorectal cancer is invariably deadly and “no patient with colorectal cancer has been cured with traditional TILs,” according to the researchers.  “Was it our cells?” McKenna asks.   “Or was it a combination of the chemotherapy the patient received plus the cells?  I think it was probably the cell therapy product.  It was a success story, and I’m sure we played a role.”  Appropriate patient selection is really important, he said, noting that the patient in question had genetic features that may have played a part in the protracted remission. 

The pioneering study was MCT’s first venture into CRISPR-Cas9 modification of cells, he said.  “It’s not like people are doing this everywhere.  We are one of a few academic centers making their own cells using CRISPR-Cas9 technology.” 

McKenna was a lead author of “Clinical manufacture of CRISPR/Cas9-based cytokine-induced SH2 protein knock-out tumor-infiltrating lymphocytes for gastrointestinal cancers” published in October in Cytotherapy.  The authors describe the three steps required to prepare the cells:  TIL from the tumor specimen are isolated and stimulated to grow; tumor cell-surface antigens (neoantigens) that serve as immune system targets are identified; and neoantigen reactive TIL undergo CISH knockout editing and are subsequently expanded in number.

In April, the University’s Center for Genome Engineering launched “Un-TIL it's Cured,” a collaboration of research scientists led by Moriarity and Webber, clinicians, non-profits, and industry to accelerate the development of TIL therapy for advanced-stage cancer.

Gene-edited TIL preparation for patients in the groundbreaking study was laborious and consequently expensive, taking 100 days from the tumor biopsy to the final product.  It is an “autologous” adoptive cell therapy.  As in the case of CAR-T, the patient’s own T cells are removed, engineered, expanded through cGMP, and reinfused.  Yet “allogeneic” adoptive cell therapy, an “off the shelf” product that can be used to treat any patient with a specific diagnosis without harvesting and engineering the patient’s cells, is showing more promise in cancer and other diseases that have a strong genetic component, diseases like muscular dystrophy.  

Off the shelf therapy products are in the offing

Take the case of MyoPAXon, a universal off-the-shelf stem cell product made by Myogenica, a University start-up company.  The University’s Masonic Cancer Center is recruiting patients for a Phase 1 clinical trial to test the safety and tolerability of MyoPAXon in individuals with Duchenne muscular dystrophy (DMD), a genetic disorder characterized by the progressive muscle loss.  That comes after years of interdisciplinary teamwork led by professor of medicine and Myogenica co-founder Rita Perlingeiro, the MCT, the Stem Cell Institute, the Center for Translational Medicine, and the Medical School’s Greg Marzolf Jr. Muscular Dystrophy Center.  Myogenica calls itself a “revolutionary, universal stem cell platform for muscle regeneration.” 

Last fall, Perlingeiro, McKenna, and fellow investigators published “Preclinical quality, safety, and efficacy of a CGMP iPSC-derived myogenic progenitor product for the treatment of muscular dystrophies” in the journal Molecular Therapies.   They reported that they had successfully developed a cGMP protocol involving selected myogenic or muscle-forming progenitor cells derived from skeletal muscle pluripotent stem cells “to generate a clinical-grade myogenic progenitor cell product, which we named MyoPAXon.”  They found no safety issues after extensive testing of the product including in mice and non-human primates. 

Last month, the Muscular Dystrophy Association issued a clinical study alert announcing a Phase 1 study of MyoPAXon in boys with DMD.

MCT has been collaborating with Perlingeiro’s research team for nearly a decade.  “We developed the GMP manufacturing methods for MyoPAXon and supplied cells for the DMD studies,” McKenna said.   Perhaps the biggest challenge is how to deliver the therapy short of multiple injections into muscle mass throughout the body, he said. Recently, scientists reported they had developed an antibody-based drug delivery strategy that successfully delivered regenerative therapy to muscle cells throughout the body in patients with myotonic muscular dystrophy, a related disease that also leads to muscle loss.  

In their study, Perlingeiro and her fellow investigators concluded that positive results from the first-in-human clinical trial now underway will enable MyoPAXon “to advance relatively quickly to the nextphases in DMD and other types of MDs” [muscular dystrophies].  If the universal off-the-shelf therapy is successful for DMD, it would constitute a remarkable advance in molecular and regenerative medicine and a godsend for some 15,000 patients and their families in the U.S.

Broadening access to cell therapy

Most FDA-approved cell therapies are for treating cancer.   Based on a recent review, more than 6,000 interventional cell therapy trials have been registered globally, with a significant shift from blood malignancies, the domain of CAR-T cell therapy, to solid tumors where TIL therapy is making strides.  CAR-NK cells, cell-based cancer vaccines , and stem cell therapies are also in the game. The push for universal off-the-shelf therapies will keep cell manufacturing facilities like MCT relevant even as patient point-of-care automated systems for CAR-T and other cellular engineering therapies are introduced in academic settings.  

Only with in vivo cell therapy – the genetic reprograming of T cells directly in a patient’s body rather than in a lab – will apheresis and cell manufacturing be circumvented.  Lipid nanoparticles were used as delivery vehicles for the successful COVID-19 mRNA vaccines.   Recently, lentiviral particles were used to generate in vivo CAR-T cell therapy in patients with blood cancers including multiple myeloma.  In April, the pharmaceutical giant Eli Lilly acquired Kelonia Therapeutics, Inc. which has pioneered in vivo CAR-T therapy for patients with relapsed refractory multiple myeloma. 

The University’s Hormel Institute in Austin has established a Viral Translation & Manufacturing Consortium (VTMC).  “It would be great to have that kind of capability here on Twin Cities campus,” McKenna said, adding that MCT is currently equipped to do small-scale viral manufacturing.  That capability may be activated soon.  McKenna said he’s been having discussions with Department of Surgery professor Julia Davydova concerning the clinical translation of oncolytic adenoviruses -- genetically engineered viruses designed to selectively replicate in and kill cancer cells while sparing healthy tissue -- for patients with pancreatic, breast, melanoma, and sarcoma malignances. 

In January, the FDA loosened requirements for cell and gene therapy manufacturers in an effort to expedite patient access.   That follows the launch last year of the Cell and Gene Therapy (CGT) Access Model by the Center for Medicare and Medicaid Services (CMS).  The model is a voluntary private program that “aims to improve the lives of people living with rare and severe diseases by increasing access to potentially transformative treatments,” with the initial focus on Sickle Cell Disease (SCD).  Writing in the New England Journal of Medicine in last month, CMS officials note that the program “leverages the collective negotiating power of participating states to secure arrangements with manufacturers of expensive gene therapies, tying price to patient outcomes.”  Thirty-two states plus the District of Columbia and Puerto Rico are currently participating.

More than a million and a half blood-forming stem cell transplants, bone marrow transplants included, have been performed worldwide since five-month-old David Camp was admitted to University of Minnesota Hospital in the summer of 1968 to undergo an experimental operation meant to save his life.  It was a true awakening that cells from someone other than an identical twin would constitute a cure.  It was, in a practical way, the beginning of cell therapy, a therapy founded on the proposition that some cells can undo or repair the damage that diseased cells have brought about and give someone with those bad cells a chance to live a normal life.  

At bottom, it was a stark reminder that, with discovery, ingenuity, and determination, the vast power of the human immune system can be harnessed to restore what has been lost.