Research highlights from the 2025 Seattle Cellular Therapy Summit

Meredith Pelster, MD, MSCI, is an Associate Director of the GI Cancer Research Program at Sarah Cannon Research Institute (SCRI). At the summit, she shares her expert insights on the epidemiology and challenges of cellular therapies for GI cancers.

Transcript

Disclaimer: This audio transcript has been edited for clarity but has been reviewed by the speaker.

Similar to some other speakers, I am not a transplanter or cell therapist by training, but I have gotten really interested in the transformative potential of cellular therapies for GI cancers. I want to talk with you about where we are and where we have to go with these therapies in GI malignancies.

Agenda

Since many of you may not be seeing a lot of solid tumor patients, I want to take just a few minutes to go over some epidemiology of GI cancers to demonstrate the scope of the problem we are dealing with. We will then discuss the challenges associated with the use of cellular therapies in GI cancers, concluding with opportunities, focusing on some biomarkers of interest and early data. This will by no means be comprehensive, but I wanted to give a sampling of some of the work that is going on.

Gastrointestinal Cancer Epidemiology

Colorectal cancers are the number three cancer type for both men and women in the US, with over 150,000 cases per year. Not included on this slide, but there has been a lot in the media about the increasing incidence in younger patients. We are seeing a huge increase in patients aged 45 and younger. It is a real phenomenon that we GI oncologists see in the clinic every day.

Looking at pancreatic cancer, we can see that this is also increasing in incidence over time and making the top 10 list. When we look at deaths, however, we see that pancreas moves up the list, coming in at number three for women and number four for men. Colorectal cancer is also on the list as a frequent cause of mortality. We see some less common GI cancers enter the list that, although not diagnosed frequently, make it here due to their high mortality rate, including esophageal cancer and liver cancer.

Colorectal Cancer Statistics

Taking a closer look at colorectal cancer as our most common GI cancer, we can see that about a third of patients are diagnosed with localized disease, generally thanks to screening colonoscopy, and those patients do have high cure rates. However, about a quarter of patients will be diagnosed at stage IV at diagnosis, and their five-year survival is only 15%. In our best prognosis subtype, which is left-sided RAS wild-type patients, the median overall survival in our most recent trial of frontline therapy was three years.

Pancreatic Cancer Statistics

The statistics for pancreatic cancer are, unfortunately, even more sobering. We can see that the five-year relative survival for all patients, regardless of stage at diagnosis, is only 12%. For those patients diagnosed with stage IV disease from the outset, it's only 3%. This makes pancreatic cancer one that is generally approached with considerable fear by patients and recognized by providers because the outcomes can be so bleak. I stress these numbers to highlight the tremendous need for new therapies, especially ones that have the potential for durable benefit with these cancers.

Immunotherapy in GI Cancers

As we begin to think about cellular therapies in GI cancers, let's first consider immunotherapy in general. Where are we with immunotherapy, particularly immune checkpoint inhibitors, in GI cancers?

We can see that in several different GI cancers, there are FDA-approved immune checkpoint inhibitors. For most of these cancers in the upper GI/biliary tract, these are in combination with frontline therapy, and the added benefit in those trials is a few months when you have an immune checkpoint inhibitor versus chemotherapy alone.

It's notable that our two deadliest GI cancers, pancreatic cancer and colorectal cancer, do not have FDA-approved immune checkpoint inhibitors unless patients have a particular molecular subtype: deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H). This has led to the perception that these are "cold" tumors and highlights some of the challenges.

Cellular Therapies

Cellular therapies utilizing T cells and natural killer cells can act as living drugs to target tumor antigens and lead to tumor cell death with the potential for durable disease control. These therapies have been revolutionary in hematologic malignancies, and there's great eagerness to translate this to GI cancers. However, there are some unique challenges.

Biological Challenges for Cell Therapy in GI Cancers

• Target Issues

Many tumor targets are also present in healthy tissues, which can lead to toxicity concerns. When we think of targets like CEA, EpCAM, etc., they are definitely present on tumor cells, but also present on healthy tissues. Another issue with targets in GI cancers is that targets can be very heterogeneously expressed, both within one tumor site and between the primary tumor and sites of metastasis.

• Tumor Microenvironment

GI cancers, particularly pancreatic and colorectal, have a notoriously immunosuppressive and hostile microenvironment. Pancreatic cancer is what comes to mind when you think about this unfavorable microenvironment - it's comprised of dense fibrotic stroma that presents a physical barrier to cells getting in. T cells that do infiltrate GI cancers face an environment that is hypoxic and acidic, with immunosuppressive cells that can lead to T cell exhaustion.

• Liver Metastases

Many GI cancers have the liver as the primary site of metastasis. We know that antigen-presenting cells (APCs) present in the liver lead to a tolerogenic environment.

• Microbiome

An interesting area of investigation is the microbiota and how the microbiome of the gut can actually inhibit immune response. There's data in melanoma about the complex relationship between the microbiome and immune system response, and we're learning about that in GI cancers as well.

Patient-Related Challenges

There are significant patient-related barriers, with performance status being the main one. Patients can progress quickly, and there are not very many GI cancer patients who have already had a couple of lines of therapy and are still fit for cellular therapy. It's hard to overstate how sick they can be, with pain, nutrition issues, and weight loss making it a real challenge. In my experience in the phase one unit, just in the short screening period when trying to get a patient onto a trial, our screen failure rate because patients develop liver failure or have dramatic changes in their performance status in just a 28-day screening period is pretty significant. Another data point: in frontline pancreatic trials, less than half of patients followed after their frontline therapy are fit enough to receive second-line therapy.

Treatment Logistics

Manufacturing timelines can be a big challenge, as can our lack of effective bridging therapies. For pancreatic cancer, we have two types of chemotherapy regimens that we typically use. If you've already used those and don't have anything in your back pocket to try to get patients to cellular therapy, that's problematic.

Opportunities: Biomarker-Driven Strategies

Despite these challenges, there are opportunities. I'll focus on biomarkers and look at data generated for select biomarkers. This is not exhaustive. There are many other interesting biomarkers (CEA, CA 19-9, mesothelin) that we don't have time to discuss.

• Claudin 18.2

Claudin 18.2 is a promising target in upper GI and pancreatic cancers. It's a tight junction protein that is aberrantly expressed on cell surfaces in malignancies. There's a monoclonal antibody called zolbetuximab approved that targets Claudin 18.2, and there are also ADCs and T-cell engagers in development.

• CT041-ST-01 Trial

The trial that has gone furthest in GI malignancies is a study of Claudin 18.2-specific CAR-T cells called satri-cel. This trial was conducted in China and included gastric cancer patients who were Claudin 18.2-positive by IHC. They had a more liberal definition of positivity (≥40% 2+/3+ IHC) compared to zolbetuximab, which requires 75% positivity. Based on encouraging phase I data, this randomized phase II trial was conducted. Patients were randomized to receive cellular therapy or physician's choice of treatment. The primary endpoint was progression-free survival. This was a large study with over 150 patients. The data was presented at ASCO this year, showing an encouraging waterfall plot with an overall response rate of 41% in the experimental group versus only 4% in the physician's choice group. The disease control rate was 81%. The survival curves for the intention-to-treat population showed improvement in progression-free survival, with quite a long tail suggesting some patients are having durable benefits. Overall survival was numerically improved as well. For safety, 95% of patients receiving cellular therapy experienced cytokine release syndrome (CRS), but only 5% were grade 3 or greater. There was no ICANS (immune effector cell-associated neurotoxicity syndrome).

• GPC3

Moving to another target, GPC3 is a membrane-associated proteoglycan that interacts with several pathways to promote oncogenesis. It's highly overexpressed in hepatocellular carcinoma (HCC), making it an exciting target.

• ORI-C101 Trial

ORI-C101 was presented at ASCO this year - it's an armored GPC3-directed CAR-T. Patients were treated in a phase I study, and at higher dose levels, there were significant responses supporting further work. One patient achieved a partial response at day 28 with a 47% decrease in target lesions, had continued shrinkage, and eventually achieved a complete response at 18 weeks that was sustained at the time of data release.

• KRAS G12D TCR

I want to discuss a different type of target, not a cell surface target, but a mutational driver target. This made it into the lay media: a report of a single-patient IND study using HLA-restricted KRAS G12D TCR in a patient with pancreatic cancer. This was reported in the New England Journal of Medicine and got significant attention. A 71-year-old woman with pancreatic cancer who was heavily pretreated received this TCR product and had a significant response. This got attention because it had potential for targeting a hotspot mutation instead of a surface protein. It's particularly exciting in pancreatic cancer, where 90% of cases have a KRAS mutation. This could be a way to excite the immune system against pancreatic cancer.

• EpCAM

Going back to cell surface targets, EpCAM is another target of interest in multiple GI cancers. It's an adhesion molecule expressed in epithelial cells of various GI cancers. Importantly, it's felt to be expressed in GI cancer stem cells, so the thought is that if this could be eradicated, it could lead to better long-term control. There are several EpCAM-targeted trials ongoing. A trial that reported data in 2023 involved an EpCAM-specific CAR with a 4-1BB costimulatory domain. This study enrolled EpCAM-positive tumors. Interestingly, patients with EpCAM-positive gastric tumors primarily have peritoneal disease and had intraperitoneal administration of the product, whereas colorectal cancers and other GI subtypes had IV administration. Twelve patients were treated. Two patients had partial responses, and two patients had persistence of cells out to 200 days.

Moving Forward: Strategies for Success

Given the multiple challenges with treating GI cancer patients with cellular therapies, different solutions will be required:

1. Addressing Target Challenges
2. Multi-specific CAR-T cells: Using CAR-T cells with multiple targets
3. Dealing with an Immunosuppressive Environment
4. Pretreatment with radiation or other interventions to change the microenvironment
5. Engineering cells to survive better in hostile environments
6. Engineering to promote persistence

Additional Considerations

• Allogeneic "off-the-shelf" CAR-T cells to reduce wait times—extremely beneficial for GI cancer patients
• Combination therapies
• Earlier treatment settings—if we treat patients when they have a very high disease burden and are already ill, we may be less successful. Looking at patients in a maintenance setting could improve success.

Current Trials at SCRI

Examples of trials in our network include:

• TCR trial targeting TP53 R175H patients
• HER2 therapy trials
• KRAS TCR trials
• ACE2016: An off-the-shelf gamma delta NK cell therapy targeting EGFR-expressing solid tumors.
  • ACE2016 is particularly interesting because these are donor-derived cells. The cytotoxic agent is conjugated to the cells by an antibody-drug conjugation, then the cells are infused into the patient, where the cytotoxic agent binds to EGFR and initiates the cytotoxic properties of these cells. Recent preclinical data showed good tumor suppression and prolonged survival in treated animals. There's an ongoing phase I trial, and I'm excited to see where that goes.

Conclusions

Cell therapy technology is expanding. There are numerous trials open to GI cancer patients looking at GI-specific biomarkers. Some early phase trials are showing preliminary safety and efficacy, but we continue to face several limitations with GI cancer patients in getting these trials to patients at the right time. I remain excited about the potential and have enjoyed discussing this topic with you all.