Harnessing the Potential of Cell and Gene Therapy

Oncology Live®Vol. 22/No. 03
Volume 22
Issue 03

Although safety remains a concern with gene therapy, investigators are breaking ground in cell and gene therapy, and many believe that ultimately, a string of cured cancers will follow.

Patrick Hwu, MD

Patrick Hwu, MD

Excitement took wing in the scientific community in the early 1990s, when the first gene therapy trial showed significant success, only to crash at the end of the decade with a patient’s tragic death.

Twenty years later, the excitement is back and greater than before. Although safety remains a concern, investigators are breaking ground in cell and gene therapy, and many believe that ultimately, a string of cured cancers will follow.

In 2017, the excitement over these therapies returned in spades when the FDA signed off on a cell-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for patients with B-cell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a person’s own T cells to attack tumor cells.

“We’re entering a new frontier,” said Scott Gottlieb, MD, then-FDA commissioner, in announcing the groundbreaking approval.

Gottlieb was not exaggerating. The growth in CAR T-cell research is exploding. Although only a handful of cell and gene therapies are on the market, the FDA predicted in 2019 that it will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.

“We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer,” said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapy’s pioneers. “It still may happen here and there, but it’ll be kind of like people dying of pneumonia. It’s like, ‘He died of pneumonia? That’s kind of weird.’ I think cancer can be the same way.”

“Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell,” Hwu said. “The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but don’t recognize the normal cells.”

Implications for the Community Oncologist

Community oncologists will need to be increasingly familiar about the various products, including their immediate and longer-term risks, Bo Wang, MD, and Deepu Madduri, MD, recently wrote in OncologyLive®.1 “It is key to understand the optimal time for referring these patients to an academic institution, as well as how to manage the requisite post CAR T-cell therapy in the community setting.” Madduri is an assistant professor of medicine, hematology and medical oncology, as well as associate director of cellular therapy service, and director of clinical operations with the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai in New York, New York. Wang is a third-year clinical fellow in hematology/oncology at Mount Sinai.

Early referral to academic centers and hospitals equipped to deliver therapies is crucial for patients eligible for therapy. However, as advances continue in the field, community practices may be called upon to administer therapies in their clinic.

The Community Oncology Alliance (COA) envisions a broader role for the settings in which CAR T-cell therapies can be administered. When the Centers for Medicare & Medicaid Services (CMS) was considering coverage for CAR T-cell therapies in 2019, COA officials argued against limiting approvals to hospitals.

“It is important to understand that there are state-of-the-art community oncology practices that have significant experience and capabilities in administering highly complex treatments,” COA officials wrote in a letter to CMS. “For example, stem cell transplants, which are similar in complexity to CAR T therapy, are performed successfully in the community oncology practice setting.”2

Broader use of gene therapies depends on several factors, including navigating the logistics of gene therapies, addressing the high costs, and managing toxicities.3

Autologous CAR T-cell therapies involve a manufacturing process that requires coordination between the treating facility and the processing facility. Following leukapheresis, patients may require maintenance therapy to control disease progression during the manufacturing time, which can take 3 to 5 weeks.

In terms of cost, gene and cell therapies can cost from $375,000 to $475,000 per dose and they may face coverage restrictions from payers. Approvals could take weeks to obtain.3,4

Because of cytokine release syndrome and neurotoxicities associated with CAR T-cell therapy, the FDA mandates risk evaluation and mitigation strategy training for centers.

Further, providers may find that real-world experiences with gene therapies are different from those seen in the clinical trial setting, according to Ankit J. Kansagra, MD.

In a presentation at the 2020 American Society of Clinical Oncology Virtual Education Program, Kansagra, an assistant professor of medicine and Eugene P. Frenkel, MD, Scholar in Clinical Medicine at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas, said that in practice patients may be older and have more aggressive disease, with double- and triple-hit lymphomas.4

Specifically, Kansagra noted that medications such as steroids and/or tocilizumab (Actemra) to prevent or treat cytokine release syndrome or other toxicities were more frequently used in the real-world setting than what had been seen in clinical trials.

As it stands now, only a fraction of eligible patients are receiving CAR T-cell therapies, Kansagra said. Potentially, 9750 patients a year may be eligible for CAR T-cell therapies in approved and upcoming hematologic indications. From 2016 to 2019, a total of 2058 patients received CAR T-cell infusion.4

Next steps for transplanting these novel therapies to clinical practice will require changes in key areas, Kansagra said, such as supply chain management, patient support, and financial systems (Figure).4

Figure. Next Steps for Effective Delivery of Gene and Cell Therapies4

Meanwhile, multiple myeloma experts advise providers to be ready for change. “As commercially available myeloma CAR T-cell therapies are approved, it will be even more important for community oncologists to better understand these therapies so they can offer them to their patients,” Wang and Madduri wrote.1

Engineering Change

Cell therapy involves cultivating or modifying immune cells outside the body before injecting them into the patient. Cells may be autologous (self-provided) or allogeneic (donor-provided); they include hematopoietic stem cells and adult and embryonic stem cells. Gene therapy modifies or manipulates cell expression. There is considerable overlap between the 2 disciplines.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvania’s gene therapy program, is cautious about the FDA’s predictions, saying she’d be “thrilled” with 5 cell and/or gene therapy approvals annually.

Juliette Hordeaux, PhD

Juliette Hordeaux, PhD

“For monogenic diseases, there are only a certain number of mutations, and then we’ll plateau until we reach a stage where we can go after more common diseases,” Hordeaux said.

“Safety has been the main brake around adeno-associated virus vector [AAV] gene therapy,” added Hordeaux, whose hospital’s program has the institutional memory of both Jesse Gelsinger’s tragic death during a 1999 gene therapy trial as well as breakthroughs by 2015 Giants of Cancer Care® winner in immuno-oncology Carl H. June, MD, and others in CAR T-cell therapy. “Sometimes there are unexpected toxicity [events] in trials….I think figuring out ways to make gene therapy safer is going to be the next goal for the field before we can even envision many more drugs approved.”

In total, 3 CAR T-cell therapies are now on the market, all targeting the CD19 antigen. Tisagenlecleucel was the first. Gilead Sciences received approval in October 2017 for axicabtagene ciloleucel (axi-cel; Yescarta), a CAR T-cell therapy for adults with large B-cell non-Hodgkin lymphoma. Kite Pharma, a subsidiary of Gilead, received an accelerated approval in July 2020 for brexucabtagene autoleucel (Tecartus) for adults with relapsed/ refractory mantle cell lymphoma.

Another CD19-directed therapy under FDA review for relapsed/refractory large B-cell lymphoma, is lisocabtagene maraleucel (liso-cel; JCAR017; Bristol Myers Squibb). Idecabtagene vicleucel (ide-cel; bb2121; Bristol Myers Squibb) is under priority FDA review, with a decision expected by March 31, 2021. The biologics license application for ide-cel seeks approval for the B-cell maturation antigen–directed CAR therapy to treat adult patients with multiple myeloma who have received at least 3 prior therapies.5

Dean A. Lee, MD, PhD

Dean A. Lee, MD, PhD

The number of clinical trials evaluating CAR T-cell therapies has risen sharply since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials. gov website. In June 2020, the site listed 671 trials, including 357 registered in China, 256 in the United States, and 58 in other countries.6 Natural killer (NK) cells are the research focus of Dean A. Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Children’s Hospital in Columbus, Ohio. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA investigational new drug application. Lee is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His efforts are geared toward pediatric sarcomas.

“The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells,” said Lee, who is also director of the Cellular Therapy and Cancer Immunology Program at Nationwide Children’s Hospital, at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital, and at the Richard J. Solove Research Institute.

COVID-19 and Other Diseases

However, Lee said, NKs have wider potential. “This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space],” he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis’ proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. Lee said the pivot toward treating COVID19 with cell therapy was because “some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.”

The revolutionary gene editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020.

For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones. National Public Radio (NPR) did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.7

“It’s a miracle, you know?” the patient, Victoria Gray of Forest, Mississippi, told NPR.

She was among 10 patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the New England Journal of Medicine.8

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Children’s Research Hospital, said, “There’s a lot of activity to really explore these therapies with diseases that are much more common than cancer.”

Stephen Gottschalk, MD

Stephen Gottschalk, MD

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence, such as conditions associated with inflammatory clots, are also being studied.

“CAR T, I think, will become part of the standard of care,” Gottschalk said. “The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off-the-shelf products to get around some of the manufacturing bottlenecks. I believe those issues will be solved in the long run.”


  1. Wang B, Madduri D. CAR T-cell therapy for multiple myeloma: what community oncologists need to know. OncLive. November 10, 2020. Accessed January 20, 2021. https://www.onclive.com/view/car-t-cell-therapy-for-multiple-myeloma-what-community-oncologists-need-to-know 
  2. Community Oncology Alliance. Proposed decision memo for chimeric antigen receptor (CAR) T-cell therapy for cancers. March 19, 2020. Accessed January 20, 2021. https://communityoncology.org/proposed-decision-memo-for-chimeric-antigen-receptor-car-t-cell-therapy-for-cancers/ 
  3. Kansgra A, Farnia S, Majhail N. Expanding access to chimeric antigen receptor T-cell therapies: challenges and opportunities. Am Soc Clin Oncol Educ Book. 2020;40:1-8. doi:10.1200/EDBK_279151
  4. Kansagara AK. Where are we now? Current landscape of CAR T-cell as standard-of-care therapy. Presented at: American Society of Clinical Oncology 2020 Virtual Education Program; August 8-10, 2020. January 20, 2021. https://bit.ly/3nbvGlN
  5. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). News release. Bristol Myers Squibb. November 16, 2020. Accessed January 11, 2021. https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Provides-Regulatory-Update-on-Lisocabtagene-Maraleucel-liso-cel/default.aspx 
  6. Wei J, Guo Y, Wang Y, et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol. Published online September 30, 2020. doi:10.1038/s41423-020-00555-x
  7. Stein R. CRISPR for sickle cell diseases shows promise in early test. Public Radio East. November 19, 2019. Accessed January 20, 2021. https://www.publicradioeast.org/post/crispr-sickle-cell-disease-shows-promise-early-test
  8. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2029392
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