Cell and gene therapies represent a revolutionary advance in personalized medicine, offering hope where traditional biologics and small molecules have struggled. Yet, these groundbreaking treatments bring unique manufacturing complexities that the industry is only beginning to truly appreciate.

David Brühlmann sits down with Chantale Bernatchez, Head of Process Development at CTMC. With two decades of experience, four patents, and a career spanning both academic discovery and industry innovation, Chantale has lived through the rapid evolution of T cell therapies—from academic cleanrooms to manufacturing at scale for game-changing clinical trials. 

Her work bridges CAR-T technology, tumor-infiltrating lymphocytes, and next-generation cell engineering—always with an eye on the practical realities of process development.

Key Topics Discussed

• Early life and education in Quebec shaping scientific foundation and research interests.
• Transition to MD Anderson in Houston for advanced postdoctoral training in tumor immunology.
• Career progression from academia to industry with increasing leadership in translational research roles.
• Leadership in cell therapy development focusing on CAR T and tumor-infiltrating lymphocyte innovations.
• Formation of CTMC through strategic partnership bridging MD Anderson and biotech manufacturing expertise.
• Innovation in process development addressing variability and optimization of patient-derived cellular therapies.
• Manufacturing complexity in CAR T and TIL therapies involving personalized production and logistical challenges.
• Challenges in quality, scalability, and future outlook including automation, standardization, and regulatory considerations.

Episode Highlights

• Personal journey: from immunology PhD in Quebec to cell therapy leadership in Houston [04:25]
• Evolution of TIL therapy at MD Anderson, including manufacturing innovations to overcome declining T cell yields [06:14]
• The fundamental differences between traditional medicines and cell-based immunotherapies [10:01]
• Unique manufacturing complexities for autologous therapies, including batch variability and process standardization [11:19]
• Strategies to address decreased cell fitness in heavily pretreated patients, including changes in cell activation and culture conditions [13:57]
• Key learnings from the CAR T and TIL manufacturing process: balancing process duration, cell fitness, and product yield [16:28]
• Mechanistic differences between CAR T and TIL therapies and their implications for efficacy and resistance [17:58]
• The limits and risks of automation in cell therapy manufacturing—balancing manual vs. automated processes [24:04]
• Why moving between manufacturing platforms raises challenges in comparability and clinical outcomes [25:44]
• The ongoing search for critical cell quality attributes that correlate with patient response [27:00]

In Their Words

The most underappreciated parameter in cell therapy process development, to me, is the variability of the starting material—whether it be tumor or apheresis material—which can lead to a large difference in T cell quality, for example between growing T cells from normal donors or patient samples. Moreover, maybe that's the most underappreciated factor: when you have heavily pre-treated patient samples, they can behave very differently than even other patient samples. So applying the same process to variable samples will give you a variable outcome—a reality that we need to live with every day.

How T Cell Activation Redefines TIL and CAR-T Manufacturing (Boosting Success Rates to 95%) - Part 1

David Brühlmann [00:00:41]:
Cell therapy has moved from a promising concept to clinical reality. But behind every successful T cell therapy lies a manufacturing challenge of extraordinary complexity. Today I'm joined by Chantale Bernatchez, who is the Head of Process Development at CTMC, a joint venture between Resilience and MD Anderson Cancer Center. Chantale is a 20-year veteran of T cell therapy with four patents in adoptive cell therapy. What does it actually take to turn a patient's own immune cells into a consistent, scalable, life-saving treatment? Let's find out.

Chantale, welcome. It’s good to have you on today.

Chantale Bernatchez [00:02:42]:
It's a pleasure to be here. Thanks for having me.

David Brühlmann [00:02:45]:
Chantale, share something that you believe about bioprocess development that most people disagree with.

Chantale Bernatchez [00:02:52]:
I will go with what I think is the most underappreciated parameter in cell therapy process development, which to me is the variability of the starting material—whether it be tumor or apheresis material—that can lead to a large difference in T cell quality, for example between growing T cells from normal donors or patient samples. And moreover, maybe that's the most underappreciated factor: when you have heavily pre-treated patient samples, they can behave very differently than even other patient samples. So applying the same process to variable samples will give you a variable outcome.

And I would say this is a big takeaway, although it seems simple. But after working in process development for many years with different patient populations or normal donor samples, that’s a reality that we need to live with every day, and I think it’s really important—and maybe underappreciated.

David Brühlmann [00:03:50]:
And this is an important point to remember, especially if you're listening and you work in biologics, where the ballgame is very different. In cell and gene therapy, you have this huge variability because every donor, every patient is different.

Before we dive further into the science and the technology, I would love to hear about your story. Chantale, can you draw us into your journey? What first sparked your interest in cell therapy, and what were some key moments along your long career that led you to your current role?

Chantale Bernatchez [00:04:25]:
Absolutely. So I grew up in Quebec, Canada—I’m Canadian. In college, I was interested in biomedical sciences. I eventually did a PhD in immunology, so I am an immunologist by training. I studied the development of T cells in the thymus. And although I thought it was fascinating, I decided that my next career step should use my knowledge in immunology and apply it to a therapeutic field.

For personal reasons, I found myself moving to Houston, Texas, as my husband had found work there. For my postdoctoral training, I was in very close proximity to MD Anderson Cancer Center, which is the largest cancer care center in the U.S. I thought it was a great opportunity to combine my deep training in immunology with applying it to finding a cure for cancer.

So I joined a tumor immunology laboratory at MD Anderson in the Department of Melanoma Medical Oncology. This was in 2007, when I started my postdoctoral training. I first worked on a project involving vaccination against cancer, but quickly joined a new program that was just starting at the time, which utilized cell therapy to treat cancer.

This program was initiated by Dr. Patrick Hwu, and it used tumor-infiltrating lymphocytes (TILs) to treat metastatic melanoma patients. I played various roles in this program over the 15 years that I spent at MD Anderson—first overseeing the production of T cells in GMP cleanrooms, and then moving on to opening my own research lab and trying to understand the correlates of response—why some patients respond to therapy and others don’t.

At the same time, I worked on expanding the number of patients eligible for this therapy by overcoming some manufacturing challenges. Even in my research lab, I was doing what we now call process development in industry. We were trying to more consistently derive T cells from tumors, even those with lower infiltration than melanoma—for example, pancreatic cancer.
As we started treating more and more melanoma patients, we had a lot of success with the therapy—up to a 50% clinical response rate. So half the patients benefited clinically, which was great. However, as more therapies became available—such as other immunotherapies, particularly checkpoint blockade strategies, and small molecules like BRAF inhibitors—patients had more FDA-approved treatment options. As a result, they came to clinical trials later, with more advanced disease.

This meant we were receiving samples from increasingly heavily pre-treated patients. We observed a steady decline in our ability to grow TILs from these tumors using the historical methodology developed at the NIH by Dr. Steven Rosenberg, where Dr. Hwu had trained before bringing the approach to MD Anderson.

So we had to optimize our methods to counteract this phenomenon and ensure we could still derive enough T cells for therapy for most patients. Gradually, we introduced manufacturing changes to improve this.

Then we turned our attention to genetic engineering of T cells. We wanted to enhance their functionality in the tumor microenvironment. We explored different strategies, such as introducing a dominant-negative receptor for TGF-beta to block its suppressive activity on T cells, or adding molecules to improve T cell migration to tumors.

Over my time at MD Anderson, I contributed to advancing cell therapy in multiple ways. When our current CEO, Jason Bock, came to MD Anderson and created a new department focused on developing cell therapy products in a more industrialized way, I was very interested in joining. It felt like a natural progression.

About a year and a half after the department was created, it transitioned into a separate entity—a joint venture between MD Anderson and Resilience, a manufacturing company. Again, I followed that trajectory, continuing to develop TIL products while also expanding into CAR-T therapies, another major T cell therapy modality that has seen more success in hematologic cancers.
Now, we’re fortunate to collaborate with both industry and academic partners developing innovative therapies. I believe we can make a real difference in shortening the time it takes for these therapies to reach clinical proof of concept. That’s really the mission of this group—to accelerate the development of these highly innovative treatments.

David Brühlmann [00:09:34]:
Yeah, that’s exciting. And what I’m also hearing is that there has been a lot going on in cancer therapies over the past several years. We now have different therapeutic options at our disposal.
Can you help us understand what fundamentally changes when we use cell-based immunotherapies—specifically using the patient’s own immune cells? You mentioned T cells and CAR-T cells. What are these cells, and how are they different?

Chantale Bernatchez [00:10:01]:
Okay, so the difference between traditional medicines like chemotherapy—which are small molecules—and cellular therapies can be understood like this: for small molecules, the manufacturer produces one batch of a therapeutic that can treat a large number of patients from that same production batch.

For cell therapy, the treatment starts with the patient and ends with the patient. Meaning we obtain either apheresis material for CAR-T cells or tumor tissue for tumor-infiltrating lymphocytes (TILs) from the patient, expand these cells ex vivo, modify their properties, and then reintroduce them into the same patient.

So one batch is now equal to one patient. That’s a very important difference. There’s a lot that goes into releasing each batch. For autologous therapies—meaning therapies where the cells come from a patient and are returned to that same patient—there is the same level of effort required for batch release, but each batch treats a different patient.

Also, because these are living therapies, they are not chemically defined products that you can simply synthesize using a machine. These therapies require special care during manufacturing. You need to optimize the conditions, and because your source material varies—since every batch starts from a different patient—applying the same process to a variable starting material will result in a variable final product.

The role of process development is to design a process that works for most, if not all, patients—finding conditions that are robust despite that variability.

David Brühlmann [00:11:42]:
And I imagine that’s quite a difficult undertaking because you have so much inherent variability. What are some strategies you’re using to develop this standard process?

Chantale Bernatchez [00:11:54]:
Yes, definitely—this is a challenge. As I mentioned earlier, for CAR-T cell therapies, because several generations of these therapeutics have already been developed, newer protocols now often recruit patients who have already progressed after a prior line of CAR-T therapy.

So you can imagine these patients have already undergone lymphodepletion and T cell therapy, and now they’re coming back for another CAR-T product. Their immune system has already been significantly challenged, and we’ve found that growing these cells in the laboratory is more difficult.
So we’ve adapted our methodologies—for example, by changing how we activate the cells or adjusting the duration of the process—to ensure we maintain or impart good functionality to these cells.

I would say that depending on the starting patient population, these adaptations will vary. This applies both to T cells derived from tumors and those derived from blood.

It has really been a challenge to keep up, because as a product matures, the patient population it targets may change. So in some cases, you need to update your process to continue robustly expanding cells from these patients.

Thankfully, as the cell therapy field evolves, there is also innovation in the reagents we use. We’ve seen developers introduce new types of reagents that are better suited for expanding cells from heavily pre-treated patients. That has been very helpful.

We need to continuously monitor and evaluate innovations in this area as well.

David Brühlmann [00:13:37]:
How do you adapt your process to the specific cell population you’re working with? Do you adjust certain process parameters—such as temperature or other culture conditions—or do you add specific components? What is your strategy there?

Chantale Bernatchez [00:13:57]:
So mainly, for decreased cell fitness coming from more heavily pre-treated patients, what we have found to be most useful is increasing the activation strength and providing better co-stimulation to the cells.

For T cells to be fully activated and able to proliferate, they need to be stimulated through their T cell receptor (TCR) and also receive a co-stimulatory signal. These co-stimulatory molecules can vary depending on the subtype of T cells you are working with.

For example, in melanoma, in our tumor-infiltrating lymphocyte (TIL) program, we initially observed that patients receiving higher proportions of a certain T cell subtype—CD8+ T cells—responded better to therapy. So we modified our culture conditions to enrich for CD8+ T cells in our final product.

To achieve this, we used TCR activation with an agonistic molecule, and we also added 4-1BB (CD137) agonistic stimulation during the early phase of TIL expansion, along with IL-2 to provide cytokine support. This approach streamlined several aspects of the process. It reduced manufacturing time, increased the yield of T cells, and increased the frequency of CD8+ T cells.

As I mentioned earlier, with heavily pre-treated patients, we saw a decline in our ability to grow TILs. Toward the end of my time at MD Anderson—around 2019, after multiple therapies had been FDA-approved and widely used in melanoma—we saw our success rate in growing enough cells for therapy drop to about 50% of patients.

After implementing our new method, we were able to bring that success rate back up to 95%. That was very significant for us.

It also allowed us to expand beyond melanoma. Melanoma is typically highly infiltrated with immune cells because it is very immunogenic, often due to mutations caused by sun exposure. But with these same process improvements, we were able to derive T cells more easily from smaller tumor samples and from tumors with lower T cell infiltration, such as pancreatic cancer.

This allowed us to move from one indication to another without needing to further modify the process, which is very valuable.

David Brühlmann [00:16:22]:
What are the typical volumes you work with, and how long does a production run last?

Chantale Bernatchez [00:16:28]:
In general, it depends heavily on the specific process. On the CAR-T side, historically, manufacturing processes lasted around 7 to 10 days. However, what we’ve learned in recent years is that shorter processes better preserve T cell fitness and maintain a higher proportion of less differentiated, more “naive-like” T cells.

As a result, many groups have moved toward shorter processes—around 3 to 5 days. This helps from a manufacturing standpoint as well. While fewer cells are generated, the cells are more potent, so lower doses can still be effective for patients.

These have been very important learnings in the CAR-T field in recent years.

On the TIL side—tumor-infiltrating lymphocytes—the process is quite different. We start with a piece of tumor tissue, and we don’t know exactly how many T cells are present in that sample. Typically, it’s a relatively small number.

Expanding enough cells for therapy takes longer, and the doses required are much higher—up to 100 billion cells, which is a very large number.

So for TILs, the end-to-end process is longer, usually around 28 days, even with recent advances.

David Brühlmann [00:17:43]:
Yeah, let’s look at the TILs—tumor-infiltrating lymphocytes—and also the CAR-T cells in more detail. What are the main differences in how they work once they are injected into patients?

Chantale Bernatchez [00:17:58]:
So CAR-T cells are engineered from the patient’s blood—specifically circulating T cells. These T cells are modified to express a chimeric antigen receptor (CAR) that recognizes a specific target on the surface of tumor cells.

Essentially, we are repurposing T cells, which normally recognize pathogens and other foreign entities, to recognize a single target with high avidity. This is because the recognition mechanism is antibody-based—the antibody moiety fused to the surface of the T cells enables this specificity. When the CAR binds its target, it triggers full activation of the T cell and induces cytotoxicity, allowing the T cell to eliminate the target cell.

These are very potent cells, but they recognize only one antigen on the tumor surface. This means tumors can develop resistance by downregulating that specific antigen, thereby escaping CAR-T cell recognition.

As I mentioned, these engineered T cells are highly effective killers. This therapy has been particularly successful in hematologic malignancies, especially B cell–derived cancers, by targeting the CD19 surface antigen. CD19 is expressed on both normal and malignant B cells, so CAR-T cells eliminate both populations. However, this type of toxicity—loss of normal B cells—is clinically manageable, for example through immunoglobulin replacement therapy.

One of the major challenges with CAR-T therapy is identifying target antigens that are uniquely expressed on tumor cells and not on normal tissues. This is especially difficult in solid tumors, where such tumor-specific antigens are rare. While some solid tumor CAR-T trials have shown promise, overall success has been more limited due to tumor heterogeneity and lack of ideal targets.
On the other hand, T cells derived directly from tumor tissue—used in tumor-infiltrating lymphocyte (TIL) therapy—are not genetically engineered to change their antigen specificity. Instead, we rely on their naturally occurring antitumor reactivity.

The immune system has evolved to generate highly diverse T cell receptors (TCRs), educated in the thymus, that can recognize a wide range of foreign antigens—including tumor-associated antigens. Tumors often express mutated or overexpressed proteins that are not present in normal cells, making them visible to the immune system.

In many cases, tumors are eliminated early by immune surveillance. However, when tumors grow, it indicates that T cells have failed to fully eliminate them.

Dr. Steven Rosenberg at the NIH made a key observation: T cells that recognize tumors are often found in higher concentrations within the tumor itself. This is because T cells migrate toward their antigen. If they cannot eliminate the tumor, they accumulate there.

TIL therapy leverages this by harvesting these tumor-infiltrating lymphocytes, which are enriched for antitumor activity but suppressed by the tumor microenvironment. We take them ex vivo, remove them from that suppressive environment, and reinvigorate them through culture—providing nutrients, cytokines, and stimulation to restore their function. At the same time, we expand them to very large numbers.

The patient is then reinfused with billions of these reinvigorated T cells, which can return to the body and attack the tumor.

The first FDA-approved TIL therapy product, approved in 2024, is an unengineered product—meaning it consists of naturally occurring T cells expanded ex vivo and reinfused into the patient.
Next-generation products aim to further enhance these cells—for example by adding cytokine support or other functional improvements—without changing their antigen specificity. This is important because one of the strengths of TIL therapy is that it targets multiple antigens simultaneously, unlike CAR-T cells, which target only one.

As a result, it may be more difficult for tumors to develop resistance to TIL therapy, since it involves a broader, multi-antigen attack.

David Brühlmann [00:23:01]:
Yeah, that’s very powerful. So there’s no doubt that these are highly potent therapies. The challenge today is really in manufacturing.

You’re working on developing standardized processes, but once you have those, you also need to think about distribution. Before we move on to that, I’d like to ask one more question about process development.

You’re dealing with tremendous variability in starting materials, and you’re trying to, in a sense, “fit” them into a production platform. I imagine that’s not easy, and that you encounter biological limits along the way. What are some of the key challenges you face?

Chantale Bernatchez [00:23:49]:
Yes, we try to standardize our methodologies for both CAR-T and TIL therapies. Over the years, these standards have evolved, and we have identified more streamlined ways to grow these cells—but there is still room for improvement. For CAR-T, the product involves fewer cells compared to TIL therapy, and there are semi-automated systems that can support manufacturing in a more controlled way. However, we are not yet at a fully automated process. Many early-phase clinical studies still rely on manual culture methods, which remain the standard in cell therapy due to the complexity of the cells.

There is still significant operator involvement required. Moving forward, we need more automation and fewer manual steps.

With the success of cell therapies, there is growing interest from instrument developers in creating fully automated manufacturing systems. Some are currently being tested, but we’re not there yet.
One challenge in process development is that fully automated systems are very expensive. Early-stage programs—especially in academia or small biotech companies—often cannot afford them. So they start with manual processes, typically using flasks, and generate clinical proof of concept.

Once efficacy is demonstrated, there is a push to scale up and streamline manufacturing. However, transitioning to a new platform at that stage carries risk. Changing the manufacturing process can alter the properties of the cells in ways that are difficult to measure or predict.

This creates a high burden of comparability—developers must demonstrate that the new process produces a product with equivalent quality and clinical efficacy.

So it becomes a bit of a conundrum: it’s difficult to start with highly automated systems, but also risky to switch to them later.

Some newer approaches aim to automate individual manual steps—essentially robotizing parts of the process—to reduce operator involvement while maintaining consistency.

We’ll see how well these approaches work over time. I think they are promising.

In cell therapy, we often say that “the process is the product,” because the manufacturing process directly influences the properties of the cells. So if you change the process, you may change the product.

That’s why, ideally, it’s better to stay with the same manufacturing platform from early development through to commercialization.

David Brühlmann [00:26:53]:
It definitely makes sense, because the process will change the product you're producing.

Chantale Bernatchez [00:26:58]:
Yes. And we don’t yet fully know all the critical quality attributes that are important for clinical response. I think it’s also important to point out that even for CAR-T cells—which have a defined target that we can measure precisely, including how effectively they recognize and kill target cells—clinical efficacy is not necessarily correlated with how well they eradicate tumor cells in vitro.
There are other properties of the cells that matter. For example, we now understand that the “cargo” of the cells—that is, the type of T cells used to carry the CAR—plays an important role. Whether the cells are more differentiated or more naive-like can significantly impact clinical response.
So I think we still have a lot to learn about the characteristics of the cells we infuse that truly correlate with clinical outcomes.

David Brühlmann [00:27:46]:
We have covered the fundamental biology distinguishing tumor-infiltrating lymphocytes from CAR-T cells, and why translating these therapies from discovery into scalable, patient-ready treatments is unlike anything else in biologics manufacturing.

In part two, Chantale goes deeper into next-generation approaches, technology transfer, and what needs to change to broadly expand patient access.

Disclaimer: This transcript was generated with the assistance of artificial intelligence. While efforts have been made to ensure accuracy, it may contain errors, omissions, or misinterpretations. The text has been lightly edited and optimized for readability and flow. Please do not rely on it as a verbatim record.

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About Chantale Bernatchez

Chantale Bernatchez is an immunologist and leading expert in T-cell therapies with over 20 years of experience spanning academia and biotechnology. She joined MD Anderson Cancer Center in 2007, where she specialized in tumor immunology and became deeply involved in adoptive T-cell therapy research. Chantale has overseen the GMP production of tumor-infiltrating lymphocyte (TIL) therapies, contributing to clinical studies in metastatic melanoma that demonstrated strong and durable patient responses. She later directed a research laboratory focused on improving TIL expansion and function.

Since 2020, she has transitioned into a biotech-focused role and now serves as Head of Process Development at CTMC, a joint venture between MD Anderson and National Resilience. In this role, she leads a multidisciplinary team advancing CAR T and TIL therapies through innovative process development and manufacturing strategies, holding multiple patents in adoptive cell therapy.

Connect with Chantale Bernatchez on LinkedIn.

Further Listening

If you’re interested in exploring further the concepts we touched on—such as cell therapy manufacturing, process control, and scaling living therapies—take a look at these related discussions:

Episodes 105 - 106: From Proteins to Cell Therapy: Why ATMPs Aren’t Just Complex Biologics with Oliver Kraemer

Episodes 109 - 110: Spinning Like Earth: Designing Low-Shear Bioreactors for Better Cell Culture with Olivier Detournay

Episodes 125 - 126: How to Enhance Cell Engineering Using Mechanical Intracellular Delivery with Armon Sharei

He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.  

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