Background and Aim
The Johns Hopkins trial, led by Drs. Marina Baretti, Nilo Azad, and Mark Yarchoan, explores an mRNA-based vaccine combined with checkpoint inhibitors. This trial aims to stimulate the immune system against cholangiocarcinoma, a type of cancer that typically evades immune detection, by addressing the known challenges in targeting “cold” tumors.
Why Cholangiocarcinoma is Hard for the Immune System to Detect: The “Party” Analogy
Imagine the immune system as a noise control team monitoring a large building, where each body cell is like a room.
- Cold Tumour (Quiet Party): Cholangiocarcinoma is considered a “cold” tumour, producing few immune signals. Think of it as a small gathering with quiet music—the immune system often overlooks it.
- Hot Tumour (Loud Party): In contrast, cancers with MSI-high or TMB-high profiles are “hot”—more like loud parties drawing immune attention due to multiple mutations and immune “flags.”
Goal of the Trial: Three Main Objectives
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- Turn a Cold Tumour into a Hot Tumour: The vaccine introduces a trio of specific antigens (CD247, FCGR1A, and TRRAP) into the tumour, making the typically “cold” cholangiocarcinoma tumour more visible and drawing the immune system’s attention as a direct target.
- Create Uniformity Among Tumour Cells: By marking each tumour cell with the same set of antigens, the vaccine provides a consistent “identity badge,” which addresses cholangiocarcinoma’s biggest obstacle to treatment: its high heterogeneity, or the differing mutations across cells. This approach helps immune cells recognise and target tumour cells more effectively.
- Clear Pathways for Immune Cell Access: Immune checkpoint inhibitors (ICIs) included in the trial aim to remove obstacles that might prevent immune cells from fully engaging with the tumour. These inhibitors block immune-suppressing proteins, allowing immune cells attracted by the vaccine to have easier and broader access to tumour cells.
Personalised Vaccine Approach: Maximising Your Body’s Response by Targeting Your Unique Tumour
This trial is not a one-size-fits-all approach. Instead, it’s tailored to each patient’s tumour profile, aiming to trigger a more powerful immune response by targeting the specific genetic “fingerprints” of their cancer. Here’s how it works:
The vaccine includes antigens that reflect mutations specific to each patient’s tumour. At a minimum, they need one mutation to target, but if more mutations are present—like KRAS or IDH1—they can add those in as well. The goal is to give the immune system several unique markers to recognise, so it’s more likely to spot and attack the cancer cells.
For example, if your tumour has an IDH1 mutation, this vaccine will be paired with Tibsovo (ivosidenib), a drug that specifically targets IDH1. This combination aims to create a clearer target for the immune system by focusing on the traits that make your tumour unique.
So, rather than trying to make your immune system work harder, this approach is about making it work smarter. It focuses your immune response on what makes your cancer different, increasing the chances of a more effective, personalised defence. This personalised strategy is discussed around the 48:21 mark in the video, where the researchers talk about the importance of incorporating as many mutations as possible into each vaccine. This way, they can leverage the full potential of your immune system’s ability to recognise and target your specific cancer.
Why Add Checkpoint Inhibitors to This Vaccine and What the Trial Aims to Achieve in Cold Tumours
This trial combines the vaccine with checkpoint inhibitors to counteract the “cold” nature of cholangiocarcinoma. Checkpoint inhibitors work by blocking PD-L1, a protein that often shields tumours from immune cells. By including these inhibitors, the trial seeks to maximise immune engagement and keep immune cells active against the tumour, effectively aiming to “keep the flame going” if the vaccine creates an initial “spark.”
Understanding Key Checkpoints: PD-L1, PD-1, and CTLA-4
In discussing immune checkpoint inhibitors, it’s essential to understand what the checkpoints are and how they function.
- PD-L1 (programmed death-ligand 1): This protein, found on some tumour cells, acts like a “healthy cell pass.” When PD-L1 is present, it binds to PD-1 on T cells, signalling them to deactivate and “stand down,” effectively suppressing immune engagement with the tumour.
- CTLA-4 (cytotoxic T-lymphocyte-associated protein 4): This checkpoint protein is typically found on T cells rather than tumour cells. It serves as a gatekeeper during early T cell activation, limiting their response to prevent overactivation. Since CTLA-4 is not expressed on tumour cells and isn’t commonly seen in biopsy samples, its inclusion in the trial focuses on early-stage immune regulation.
Together, PD-L1, PD-1, and CTLA-4 function as “security guards” that control immune engagement, allowing tumours to evade a full immune response. Checkpoint inhibitors block these interactions, helping immune cells recognise and more effectively attack cancer cells.
Supporting Evidence on Antigen Selection
Studies suggest that antigens CD247, FCGR1A, and TRRAP correlate with immune cell infiltration, theoretically aiding immune activation against cholangiocarcinoma. However, evidence for their effectiveness remains largely theoretical, primarily based on preclinical studies.
Key Limitations You Should Be Aware Of
- Non-Specific Targeting: This vaccine’s delivery system, called lipid nanoparticles (LNPs), spreads mRNA broadly across cells in the body—not just cancer cells. While this spreads the vaccine widely, it also means healthy cells might take it up, causing effects they can’t fully predict. Right now, there’s no way that they can make sure it only goes to the tumour cells.
- Immune Response Remains Theoretical: Although this vaccine aims to stimulate the immune system, there has been no solid proof in actual patients that this will work. So far, it’s based on lab results, which means the actual immune effect is unknown.
- Checkpoint Inhibitors May Have Limited Impact: Since cholangiocarcinoma usually shows low levels of PD-L1 (a checkpoint inhibitor target), the added checkpoint inhibitors may not have as strong an effect in boosting the immune system as they would in cancers with higher PD-L1 levels.
Trial Details
- Location: Johns Hopkins Sidney Kimmel Comprehensive Cancer Centre
- Principal Investigators: Drs. Marina Baretti, Nilo Azad, and Mark Yarchoan
- Eligibility: Patients with cholangiocarcinoma who have received at least one prior treatment, including chemotherapy or immunotherapy
- Vaccine Administration: Delivered through three injections at different body locations (arms and a leg), administered weekly and later spaced to monthly intervals.
- Checkpoint Inhibitors: Administered via IV to potentially support and sustain any immune activity triggered by the vaccine.
This trial represents an experimental approach combining mRNA technology with checkpoint inhibitors to enhance immune detection and targeting of cholangiocarcinoma cells. It is designed to be a promising yet exploratory step forward, and patients are encouraged to consider both the innovative aspects and potential risks in consultation with their healthcare team.
About the Antigens
CD247 (CD3 zeta chain): CD247 works like a “call to action” for T-cells, which are the body’s main immune defence cells. Once activated, CD247 pushes these cells to hunt down and target cells that might be a bit off. Essentially, it nudges the immune system to recognise and deal with any cells that seem out of place, like a quiet reminder that something isn’t right.
FCGR1A (CD64): FCGR1A is like the immune system’s bridge to antibodies. Antibodies mark harmful cells, and FCGR1A binds to them, which puts a spotlight on the cells the immune system needs to destroy. It’s like a big, bold arrow pointing out the tumour cells, making it clearer where the immune system should focus its attention.
TRRAP (Transformation/Transcription Domain-Associated Protein): TRRAP works a bit like a stabiliser, ensuring immune cell “messages” get through clearly and smoothly. It helps immune cells talk to each other properly and keeps responses steady, potentially making it easier for the immune system to spot and respond to tumour cells without overreacting or missing the target.
Balancing Hope with Reality: The Long Shot of a Clinical Trial
This trial represents a hopeful opportunity for many—it’s an innovative attempt to make cholangiocarcinoma more visible to the immune system, which is something this cancer typically evades. However, it’s equally essential to keep in mind that this is an early-stage effort with no solid proof of its effectiveness in patients yet. The approach is based on theoretical foundations, lab research, and preliminary data