Cell-Based Medicine

by Elliot Hershberg & Andrew Pannu

Cell therapy works through growing pains

It's an understatement to say that cell therapy has come a long way. In under 20 years, the space has produced 6 FDA approved therapies with >$5B in aggregate sales, spawned 150+ companies pursuing 650+ development programs and garnered >$200B in cumulative public & private investment. 

However, it has also faced its share of criticism. Approved drugs are seeing growth stall as concerns grow around the prohibitive cost, the necessity in the treatment paradigm as bispecific antibodies (bSAbs) and other more portable treatments emerge and inequity in access. A number of companies are struggling to raise or have already shut down, sometimes in fire sales.

Compared to the evolution of other modalities (such as mAbs), cell therapy's growth at a similar time point is astonishing, but perhaps early success set expectations too high.

It's our belief that cell therapy is simply working through its growing pains. The game changing potential to reprogram our cellular biology to fight disease persists - and emerging scientific breakthroughs promise to propel the space to new heights, particularly around in vivo delivery, alternative cell types and new indications, especially in autoimmune disease. 

This theme looks to highlight some of that amazing innovation, while also acknowledging the challenges to come.

Paper one

CAR T-cell therapy in autoimmune diseases

by Georg Schett, MD; Andreas Mackensen, MD; Dimitrios Mougiakakos, MD


While engineered immune cells have mostly been used to treat cancers, we are now seeing their incredible potential in autoimmune diseases such as lupus. This is a pivotal shift from immunosuppressive therapies to more precise, cell-based strategies that offer hope for durable remission and improved quality of life for patients refractory to current treatment options. 

Methods and results

Prior research has shown that control of autoimmune diseases is correlated with deep B-cell depletion, but current treatments do not fully eliminate circulating B-cells, particularly within the tissues1. CAR-T cells are a promising option in this case due to their high-affinity specific target binding, ability to infiltrate, expand and survive in the tissues and established efficacy against malignant B-cells with multiple FDA approvals2.

Phases and challenges of treatment with autologous CAR T cells in autoimmune diseases.

CD-19 directed CAR-T cells were used for the first time in 2021 in the treatment of a 20-year old woman with severe, treatment-refractory SLE. The infusion was well tolerated by the patient and delivered complete clinical remission after 3 months, with successful discontinuation of immunosuppressive agents without signs of disease up to 18 months3. Additional studies in patients with SLE showed similar promising results, with rapid cessation of clinical manifestations and stable production of CD19 CAR-T cells4

Importantly, no long-term B-cell aplasia was observed as B cells reconstituted around 100 days after the infusion. B-cell recurrence after CAR-T cell therapy was not associated with disease recurrence, which contrasts with treatment with conventional agents such as rituximab, which saw B-cell recurrence correspond with flares of SLE.

Paper two

A big step forward for logic-gated cell therapy

by Aidan M. Tousley, Maria Caterina Rotiroti, Louai Labanieh, Lea Wenting Rysavy, Won-Ju Kim, Caleb Lareau, Elena Sotillo, Evan W. Weber, Skyler P. Rietberg, Guillermo Nicolas Dalton, Yajie Yin, Dorota Klysz, Peng Xu, Eva L. de la Serna, Alexander R. Dunn, Ansuman T. Satpathy, Crystal L. Mackall & Robbie G. Majzner


CAR-T therapy has already delivered life-changing results for patients with blood cancers. Despite the early success, there is room for new receptor designs—to improve performance and to expand into solid tumor treatment.

A new study from leading labs at Stanford University and the Parker Institute demonstrated meaningful advances in the ability to encode boolean logic into CAR-T cell receptors.1

Methods and results

The first generation of chimeric antigen receptors have a fairly simple design. They consist of an antibody receptor—primarily targeting CD19 to-date—and the intracellular CD3ζ domain of a T-cell receptor.2

While this design achieves antigen targeting and T-cell activation, what if we could also encode logic that dictates specifically when cells are activated?

This study surveyed a wide range of new intracellular receptor components to achieve this. One example is a new design with two receptors that only activates when bound to CD19 AND HER2. Additionally, a different set of intracellular domains is used that circumvents the upstream signaling required by the CD3ζ domain.

The designs tested in this study showed impressive performance relative to previous attempts at logic-cated T-cell therapies in the literature.

Paper three

Pooling screening for cell-based therapy design

by Franziska Blaeschke, Yan Yi Chen, Ryan Apathy, Bence Daniel, Andy Y Chen, Peixin Amy Chen, Katalin Sandor, Wenxi Zhang, Zhongmei Li, Cody T Mowery, Tori N Yamamoto, William A Nyberg, Angela To, Ruby Yu, Raymund Bueno, Min Cheol Kim, Ralf Schmidt, Daniel B Goodman, Tobias Feuchtinger, Justin Eyquem, Chun Jimmie Ye, Julia Carnevale, Ansuman T Satpathy, Eric Shifrut, Theodore L Roth, Alexander Marson


So far, engineered T-cell therapies have made one change: the addition of a new receptor.

A clear North Star for the field of cell-based medicine is to expand the complexity and scope of cellular designs. Testing more complicated designs is a hard problem.

This new study introduces a modular screening platform to test a massive number of genetic knock-in (KI) sequences to program new functions.

Methods and results

Testing the function of large sets of synthetic DNA sequences in cells—especially in combination—is a challenging genetic engineering problem. It’s difficult to systematically add many different DNA regulatory elements or new surface receptors in a single experiment and keep track of what each sequence is doing to the cells.

This is where the beauty of DNA barcoding comes in. By labeling a library of sequences with short nucleic acid identifiers, it’s possible to conduct large screens in a pooled fashion, where all of the results are read out at once—and then separated in analysis using the barcodes.

With this clever genetic engineering approach, the authors were able to screen a library of ~10,000 new DNA designs in different T-cell therapies. This study focused on new elements that helped T-cells avoid exhaustion, which is one of the major limitations of current medicines in the clinic.

This screening platform should be broadly useful for cell programming.

Paper four

Engineered skin bacteria program T-cells to attack cancer

by Y Erin Chen, Djenet Bousbaine, Alessandra Veinbachs, Katayoon Atabakhsh, Alex Dimas, Victor K Yu, Aishan Zhao, Nora J Enright, Kazuki Nagashima, Yasmine Belkaid, Michael A Fischbach 


T-cell therapy is complex. A patient’s cells are removed from their body, engineered, and then reintroduced. Much of the field’s current focus is on streamlining this process and improving the engineering step.

But what if the future of cell therapy looked totally different?

A study from Stanford University engineered microbes on the skin to trigger a cancer-killing response from T-cells.

Methods and results

CAR-T therapy is an autologous treatment, meaning that the final medical product consists of a patient’s own cells. This is a powerful new paradigm, but introduces considerable logistical complexity into the treatment process. A patient’s T-cells are isolated, transformed with genetic engineering, and then returned to the blood.1

Many labs and companies are developing engineering solutions to simplify this process, making it faster and more affordable.

But what if there are entirely different avenues for programming T-cells to attack cancer cells?

A study from Stanford University demonstrated one possible alternative. Researchers engineered microbes naturally present on the skin to express cancer antigens on their surface. Remarkably, T-cells sampled these antigens and migrated to attack and kill cancer cells.

Imagine a future where T-cell therapy is as simple as applying a lotion to your skin.

Paper five

Continued progress in CAR constructs for macrophage therapies

by Anhua Lei, Hua Yu, Shan Lu, Hengxing Lu, Xizhong Ding, Tianyu Tan, Hailing Zhang, Mengmeng Zhu, Lin Tian, Xudong Wang, Siyu Su, Dixuan Xue, Shaolong Zhang, Wei Zhao, Yuge Chen, Wanrun Xie, Li Zhang, Yuqing Zhu, Jing Zhao, Wenhong Jiang, George Church, Francis Ka-Ming Chan, Zhihua Gao & Jin Zhang


The first immune cells engineered with chimeric antigen receptors (CARs) were T-cells. In the next generation of approaches, researchers have experimented with other immune cell types, including macrophages.

In this study, CAR macrophages with more sophisticated receptors showed substantial improvements over the first generation of this therapy.

Methods and results

This work describes the development of second-generation CAR macrophages derived from induced pluripotent stem cells. These cells have been engineered with enhanced capabilities to target and kill cancer cells, thanks to a dual signaling system that combines a traditional CD3ζ with a toll-like receptor domain.

This design allows the macrophages to better recognize and eliminate tumor cells, resist alternative activation, and manipulate the tumor environment effectively. The results demonstrate significantly improved anti-tumor functions compared to earlier versions, suggesting potential for more effective use of additional immune cells beyond T-cells.

Paper six

Early clinical results for GD2-targeting CAR-T cells in glioma patients

by Robbie G. Majzner, Sneha Ramakrishna, Kristen W. Yeom, Shabnum Patel, Harshini Chinnasamy, Liora M. Schultz, Rebecca M. Richards, Li Jiang, Valentin Barsan, Rebecca Mancusi, Anna C. Geraghty, Zinaida Good, Aaron Y. Mochizuki, Shawn M. Gillespie, Angus Martin Shaw Toland, Jasia Mahdi, Agnes Reschke, Esther H. Nie, Isabelle J. Chau, Maria Caterina Rotiroti, Christopher W. Mount, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Courtney Erickson, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Sreevidya Kurra, Katherine E. Warren, Snehit Prabhu, Hannes Vogel, Lindsey Rasmussen, Timothy T. Cornell, Sonia Partap, Paul G. Fisher, Cynthia J. Campen, Mariella G. Filbin, Gerald Grant, Bita Sahaf, Kara L. Davis, Steven A. Feldman, Crystal L. Mackall & Michelle Monje


The early antigen target of CAR-T cells for blood cancers was CD19. CD19 is a universal marker of B-cells, which are capable of completing regenerating after being eliminated during a course of CAR-T therapy.

An open question for the next generation of CAR-T therapies has been what additional targets will be viable beyond CD19. In new clinical results in glioma patients, CAR-T cells targeting GD2, which is highly expressed in a subset of cancers, the field saw early signs of promise for a novel target with sufficient specificity and safety.

Methods and results

This study describes the results of a Phase I clinical trial using GD2-CAR T cell therapy for treating diffuse midline gliomas with H3K27M mutation, a challenging type of brain cancer in children and young adults. The therapy involves engineering T cells to target GD2, a molecule highly expressed on these tumor cells.

Results showed that some patients experienced significant clinical and radiographic improvements with manageable side effects related to inflammation. These findings suggest potential for CAR-T therapy in treating a solid tumor with a novel genetically informed antigen target for the receptor.

Author's Opinion

While it’s still early days for the field, one thing is clear: cell-based therapies are here to stay. Between microbes, stem cells, and immune cells, we are likely only scratching the surface of what is possible.1

As we’ve covered in this report, researchers are hard at work building more sophisticated cellular designs. We are learning how to bake boolean logic into cell circuits, and how to test new designs at a massive scale using the powerful read/write/edit tools of modern synthetic biology.

Beyond cellular design, the future of cellular delivery could also look completely different.2 Many labs and companies are developing new solutions for dramatically improved ex vivo cell therapy, and a new wave of in vivo approaches—ranging from mRNA programming to engineered skin microbes—are right around the corner.

As these new technologies make their way into the clinic, we expect that cell-based therapies will expand across blood and solid cancers, autoimmune indications, and beyond.

Policy impact one

FDA requires classwide box warning for CAR-T products

by Angus Liu


Kymriah, the first CAR-T product to gain FDA approval, only entered the market six years ago. We are still in the earliest innings for cell-based medicine, and still have little longitudinal patient data to understand potential risks. The FDA has decided to adjust the product labels for these medicines accordingly.


On January 19th, the FDA issued warning letters to the makers of all six of the CAR-T therapies that are currently on the market. The agency now requires that the companies producing these medicines update their warning labels to include the potential for T-cell malignancies.

The concern is that engineered T-cells could have a higher risk of becoming malignant, leading to the formation of secondary cancers for patients.

While the complexity of cell-based therapies is new, leaders in the field argued that the value provided still greatly outweighs the risks, even relative to other medicines.1 Empirically the “rate of T-cell malignancies observed is far lower than that seen with some other treatments.”

As more patients are treated with cell-based therapies in the coming years, our understanding of their side effects will expand, offering new opportunities for improvement.

Policy impact two

Difficult path to genericization / biosimilars

by Peter Kolchinksy


How do we drive down drug prices (add to “armamentarium”) if it’s very hard to replicate manufacturing? This article proposes a synthetic genericization mechanism that protects society from “forever monopolies” that may become more common in an era of complex cellular medicines. As our industry moves in that direction, it’s important we have these self-regulating conversations around pricing, monopolies and the fair patent life of a drug - otherwise, external players will impose regulations upon on, which will likely damage innovation as it misses important nuance.


The double edged sword of cellular medicines is that their curative potential mixed with incredibly complex bioengineering and manufacturing means that traditional “genericization” is much more difficult. 

The Biotech Social Contract stipulates that companies should receive a fair, but not indefinite, period of time to recoup their investment and turn a healthy profit - but once that period ends, society will get that drug at a fraction of the cost as cheaper copycats flood the market. This works well with a small molecule oral pill, but not so much for CAR-T cell therapy. So what can we do to ensure the social contract is upheld?

Peter proposes a synthetic genericization mechanism whereby the company producing that cellular medicine is forced to transfer know-how to 2-3 other manufacturers to ensure price competition and supply redundancy. Such a transfer increases confidence that a copycat version is identical to the original, particularly as the manufacturing complexity of these medicines means this is not a simple task.

It’s also important to remember that new branded drugs may disrupt these cellular medicines in a very similar fashion - with better efficacy, safety, dosing, convenience, etc. and those medicines themselves may be more easily generalizable - so it’s not a given that synthetic genericization needs to occur every time, just that it’s an important backstop for society should we need it.

Challenge one

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

by Xiamon Zhang, Hui Zhang, Huixuan Lan, Jinming Wu, Yang Xiao


While an incredible option for patients, the realities of CAR-T accessibility, manufacturing and cost forces us to consider the question: is it possible to overcome the many barriers that prevent widespread use of this treatment?

Only by acknowledging the many deficiencies can we start to build a network of solutions that ultimately bring life-saving drugs to more patients


Anti-BCMA CAR-T therapies have achieved impressive clinical outcomes in relapsed or refractory multiple myeloma (r/r MM), but there are several challenges that limit accessibility. 

The current personalized manufacturing process for commercial CAR-T products takes 3-4 weeks and is extremely expensive. Patients suffering from rapid disease progression sometimes cannot afford to wait this long for treatment. Additionally, this therapy is typically delivered in an inpatient setting at a large academic medical center [1], which creates geographical & cost barriers to access.

To address these challenges, several novel approaches are being tried:

  • Bridging therapies to limit progression while treatments are prepped
  • Rapid manufacturing platforms such as FasT CAR-T cells, which can be produced in 24 hours [2]
  • Allogeneic (“off-the-shelf”) therapies
  • Utilizing non-viral transfection
  • Initiating treatment earlier for high-risk patients

Challenge two

Manufacturing Challenges in Cell Therapy

by Jan Debaere, Glenn Van Dael, Kevin Missault, Natalia Moretti Violato, Alexander Dietrich, Theodoros Marioglou


The number of companies pursuing cell therapy has exploded the past few years, but most are still relying on entirely bespoke processes for small batch early-stage trials. As the industry progresses towards the pivotal & commercial stage, there is a clear need to develop robust & scalable manufacturing processes to alleviate supply bottlenecks and bring down costs.


  • CGT has produced a novel manufacturing approach that still closely mirrors academic research (open handling, manual labor, inefficient equipment use), all contributing to costs >$100K per treatment
  • Autologous therapies are inherently limited to one unit batches and this is still the dominant approach
  • Patients are generally late-line and thus the variability in the quality of starting material is a big challenge to producing a final product on the other end of the process
  • Researchers and companies are addressing these limitations with a variety of approaches, including single cell processing devices, decentralized manufacturing, non-viral gene transfer methods, novel QC testing methods and allogeneic therapies
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