By Dr. Manuel Litchman, CEO, and Dr. Knut Niss, CTO, Mustang Bio
Last October, the FDA placed a clinical hold on all Allogene Therapeutics’ AlloCAR-T clinical trials after a chromosomal abnormality was found in a patient who had received its anti-CD19 CAR-T candidate. While the FDA hold has since been lifted,1 the event itself raises questions about what the FDA and EMA might eventually require for product clearance. Because of these uncertainties, the shiny new penny of allogeneic CAR-T therapies has likely lost some of its luster.
Following the publication of the first preclinical studies of allogeneic CAR-T cell cancer therapies about five years ago, an appealing narrative began to take hold – this “off-the-shelf” CAR-T would inevitably replace the pioneering autologous CAR-Ts. By 2020, numerous major companies and start-ups were focusing on allogeneic CAR-T therapies. In one survey, nearly half of respondents pointed to allogeneic immunotherapies as the next big thing in cell therapies.2 This narrative endures, even though allogeneic CAR-Ts have not demonstrated superior efficacy or safety vis-à-vis their autologous counterparts and their promise of lower cost of goods does not appear to have been realized.
Given recent developments, the assumptions and perceptions about both autologous and allogeneic CAR -T therapies warrant a closer look.
The Modern Miracle of Autologous CAR-Ts
The ever-quickening pace of scientific discovery can make years seem like decades. Though autologous CAR-T therapies are now part of the standard of care for multiple blood diseases, less than 10 years ago they were being hailed as a miracle of modern science. Perhaps you recall the story of Emily Whitehead, who was diagnosed with acute lymphoblastic leukemia (ALL) at the age of five and, after two relapses, was recommended for hospice care and expected to live only two weeks. In April 2012, she became the first pediatric patient in the world to receive a CAR-T cell therapy. Nearly 10 years after her one and only infusion of CAR-T cells, Emily remains cancer-free.3
In 2013, Science recognized CAR-T and other cancer immunotherapies as the “Breakthrough of the Year.”4 Four years later, the FDA approved 2 autologous CAR-T cell therapies for patients with certain types of hematologic cancers: relapsed or refractory ALL and relapsed or refractory large B cell lymphoma. To date, autologous CAR-T therapies have received six approvals across five products.
Unanswered Allogeneic CAR-T Questions
Although the full impact of the FDA’s hold on Allogene’s AlloCAR-T clinical trials and its ongoing investigation may not be known for years, these developments raise concerns and questions to all allogeneic CAR T therapies that could slow or impede their development. These include:
- Understanding and managing the risk of chromosomal aberrations -- no currently available assay can provide 100% assurance that no aberrations are present in a therapy’s potentially hundreds of millions of cells. Although the evidence thus far indicates the aberration in the Allogene patient did not cause harm, this may not always be the case with other aberrations in other patients.
- Quality control – after a product is made, what methods can be used to ensure the gene editing process has done the work and 100% of the cells in the infused product have undergone successful gene editing? Since the process is far from perfect, theoretically as many as several million unedited naïve T-cells from a third party could be present in a dose given to patients.
- Durability – the immunologic mismatch between donor and recipient can create problems such as host-versus-graft response, since patients still have some immunity and their cells can attack the allogeneic CAR-T cells. This immunity may diminish the efficacy of allogeneic CAR-T cell therapies and could explain why they often require repeat dosing.
- T-cell exhaustion – The goal of an allogeneic approach is to make as many doses as possible. This requires an extended time of expansion that has the potential to increase the risk of T cell exhaustion, a progressive loss of effector function and memory potential that can adversely affect activity.
- Qualifying incoming material/batch-to-batch variability – The critical quality attributes of CAR-Ts are currently poorly understood, which makes it hard to define any specifications for the starting T cell population. However, this will be critical to avoid batch-to-batch variability. At a minimum, allogeneic CAR-T therapies will have to test multiple separate (i.e., derived from different donors) batches of product for consistency.
Autologous CAR-Ts: Clear Regulatory Pathway, Proven Safety Profile, Validated Targets
Conversely, the regulatory path and the FDA’s CMC requirements for autologous CAR-Ts are well understood. Commercial autologous therapies, as well as those still in clinical development, have consistently demonstrated an excellent safety profile and durable responses. Many have validated targets such as CD20 and CD19 to treat high-risk B-cell non-Hodgkin lymphomas, chronic lymphocytic leukemia, and other blood cancers. Therapies for these two targets have shown unprecedented results in patients without curative options.5
These factors are instrumental in de-risking autologous CAR-T development for companies such as Mustang Bio, our clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors, and rare genetic diseases. By leveraging our core competencies in translational science, clinical development, and operational execution – and by partnering with world-leading academic institutions – we are building an extensive pipeline of next-generation and potentially first-in-class therapies. Several major academic centers are conducting clinical trials with our drug candidates, which include:
- MB-106 – which targets CD20 and is generating encouraging results in B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia (CLL), the latter of which does not have an approved CAR T therapy. MB-106 data presented at the 63rd American Society of Hematology Annual Meeting in December 2021 by Mustang’s collaborator Fred Hutchinson Cancer Research Center (Fred Hutch) demonstrated 95% ORR, 65% CR rate and no CRS or ICANS ≥ grade 3.6
- MB-101 – which is intended to treat brain cancer tumors and targets IL13Rα2, an attractive CAR T target since its expression is elevated on the surface of most malignant glioma cells. Although glioblastoma is among the most lethal of human cancers, one patient in a Phase 1 MB-101 study by City of Hope (a Mustang Bio collaborator) was tumor-free for 7.5 months,7 and a second patient in that same trial has been tumor-free for more than 30 months.8
- MB-105 – which targets prostate stem cell antigen (PSCA) and is being investigated in one of the first CAR-T trials for prostate cancer in the nation taking place at City of Hope.9 In initial data presented in October 2020, a 73-year-old male patient with PSCA-positive metastatic castrate-resistant prostate cancer who was treated with MB-105 and lymphodepletion (a standard CAR-T pre-conditioning regimen) after failing eight prior therapies experienced a 94 percent reduction in prostate-specific antigen (PSA) on day 28, with near complete reduction of measurable soft tissue metastasis by computerized tomography and improvement in bone metastases by magnetic resonance imaging.10
- MB-102 – which targets CD123 on the surface of tumor cells in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare disease similar to acute myelogenous leukemia for which there is only one FDA-approved therapy. A Phase 1 trial of MB-102 at City of Hope demonstrated a complete response at the starting dose level in a patient with refractory BPDCN,11 thereby supporting Mustang Bio’s decision to initiate its current Phase 1 multicenter trial.
Dispelling Capacity Concerns in the Manufacturing of Autologous CAR-Ts
Any discussion regarding the commercialization of cell and gene therapies inevitably includes the challenges of manufacturing them at scale. In fact, concerns about autologous CAR-T therapies’ perceived shortcoming in this regard probably contributed to the appeal of the off-the-shelf promise of allogeneic CAR-Ts. Although early cell processing methods for autologous CAR-T therapies took longer than desired, recent developments have greatly improved the efficiency of producing autologous CAR-Ts, as well as the quality of the final product.
Unlike most biopharma start-ups focused primarily on research, Mustang Bio’s efforts from day one have centered on how we could streamline developmental and cell manufacturing processes. Today, more than half of our 100 employees are involved in cell processing, which is the most labor-intensive, complicated, and costly aspect of developing a cellular drug product.
A cornerstone for our growth is our 27,000 square foot cell processing and translational research facility on the University of Massachusetts Medical School campus, which was designed to optimize facility utilization and minimize operator time. Importantly, it enables us to operate completely independent of any third-party, not just for manufacturing but also with respect to quality control. This frees us from having to rely on manufacturing slots from contract development and manufacturing organizations (CDMOs), which are costly and not always available. Also, if something were to go wrong with a process validation at a CDMO, we would need to wait until the CDMO had the capacity and people available for a rerun. By contrast, if a process validation should ever fail in our own facility, we could start it again within a week.
While most pharma facilities make only one product, the cleanrooms in our facility can be used for multiple products and are designed to address the unique aspects of autologous CAR-Ts. For example, since incubation can easily account for over 90% of manufacturing time, our facility facilitates faster cleanroom turnover, which expands capacity without adding physical space.
We have reduced the cell processing steps to a minimum and are aggressively looking at new technologies that could make our processes even more efficient.
What’s Next? Potential “Off-the-shelf” Autologous Therapies for Hematologic Malignancies
On the developmental side, Mustang Bio has the unique approach of in-licensing potential first-in-class therapeutic assets post-discovery from leading academic institutions to mitigate portfolio risks and maximize the likelihood of success. In addition to City of Hope and the Fred Hutch, we have licensed technology from Nationwide Children’s Hospital, St. Jude Children’s Research Hospital, Mayo Clinic, and Leiden University.
One of the most promising new developments is our exclusively licensed platform from Mayo Clinic to create CAR-T therapies in the patient – rather than in a cell processing facility – with potential application for any tumor target. As has already been demonstrated in an animal tumor model, this novel platform creates these therapies in two steps:
- First the patient receives an injection into the skin of a genetically engineered adenovirus that drives activation of T cells in local lymph nodes.
- A viral CAR construct is then infused directly into these lymph nodes to infect the activated T cells and thereby create CAR-T cells in the patient. These CAR-T cells then leave the lymph node, circulate in the patient’s body, proliferate, and kill tumor cells.
If successful, this platform could lead to off-the-shelf CAR-T therapies by eliminating the need to isolate and expand patients’ T cells ex vivo. Functionally speaking, the platform could represent the future of “allogeneic” therapies. We expect it to be a robust discovery engine for Mustang Bio within the next several years.
Final Word: A Dire Need for all Types of Cell and Gene Innovations
It should be noted that Mustang Bio also has a stake in advancing transformational ex vivo lentiviral gene therapies with our MB-107 and MB-207 candidates for X-linked severe combined immunodeficiency (XSCID), which have been licensed from St. Jude and are currently being currently assessed in two Phase 1/2 clinical trials: A 3-center study in newly diagnosed infants under the age of two led by St. Jude12 and a single-center study in previously transplanted patients at the National Institute of Allergy and Infectious Diseases.13
While the ascendancy of allogeneic CAR-T therapies is no longer a foregone conclusion, they undoubtedly will continue to play a role in addressing an array of unmet needs in patients with cancer. No cell and gene therapy, including autologous and allogeneic CAR-Ts, is suitable for all patient populations and situations. But everyone in our field shares the same goal: to bring safe and innovative treatments to patients who lack meaningful therapeutic options. As a former practicing oncologist for 24 years, our colleague Bruce Dezube, M.D., Senior Vice President and Head of Clinical Development, speaks to the empathy and passion that drives our efforts:
“It’s a humbling experience to have to tell patients there’s nothing more we can do. As I was leaving my practice, one of them said to me, ‘I’m not happy you’re leaving, but when I think that you will be developing a drug for when my disease relapses, I forgive you.’ Then she put her face one inch away from mine and said, ‘Always remember my face and make sure you develop a new drug for me.’ I made a vow to her and all my patients to not just extend their life but to improve their quality of life. And I still see her face every time I think about MB-106.”
- Allogene Therapeutics Announces Removal of FDA Clinical Hold Across All AlloCAR T™ Clinical Trials. Allogene Therapeutics press release. January 10, 2022. Allogene Therapeutics Announces Removal of FDA Clinical Hold Across All AlloCAR T™ Clinical Trials. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-removal-fda-clinical-hold-across
- Stanton, Dan. CAR-T at the Crossroads: Is Allogeneic the Way to Go? BioProcess International, January 30, 2020. CAR T-cell Therapies: Allogenic the Way to Go? - BioProcess InternationalBioProcess International (bioprocessintl.com)
- Emily’s Story. The Emily Whitehead Foundation. Our Journey | Emily Whitehead Foundation
- Coontz, Robert. Science's Top 10 Breakthroughs of 2013. December 19, 2013. Science's Top 10 Breakthroughs of 2013 | Science | AAAS
- Martino M, Alati C, Canale FA, Musuraca G, Martinelli G, Cerchione C. A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia. Int J Mol Sci. 2021;22(4):2150. Published 2021 Feb 21. A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia (nih.gov)
- Mustang Bio Announces Updated Interim Phase 1/2 Data for MB-106 in Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Mustang Bio press release. December 13, 2021. Mustang Bio Announces Updated Interim Phase 1/2 Data for MB-106 in Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
- Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy | NEJM
- Brown CE. First Annual Conference on CNS Clinical Trials, October 1, 2021.
- Mustang Bio Announces Initial Phase 1 Data on MB-105 for Patients with PSCA-positive Castration Resistant Prostate Cancer. Mustang Bio press release. October 26, 2020. (Mustang Bio Announces Initial Phase 1 Data on MB-105 for Patients with PSCA-positive Castration Resistant Prostate Cancer)
- Blood (2017) 130 (Supplement 1): 811. (https://doi.org/10.1182/blood.V130.Suppl_1.811.811)