Cholangiocarcinoma Vaccine Opportunity

Evaluating and Understanding the New Cholangiocarcinoma Vaccine Trial: A Patient-Centric Analysis

By Steve Holmes

This review breaks down the information provided in the video below, covering the new cholangiocarcinoma vaccine trial at Johns Hopkins. The goal here is to empower patients and caregivers with a clear understanding of the trial’s objectives, mechanics, and limitations.

But as we explore these facts, I want to invite you to test your thinking and engage deeply. I work hard to keep this analysis professional, but my priority remains with the patient and caregiver as the primary reader. Fiction often precedes reality. Or, put another way—hope is real. It provides a bridge across the unknowns and chaos to a new reality waiting for us on the other side. We simply need to begin the journey.

This isn’t just about understanding a new treatment’s objectives and details; it’s about navigating each step with a grounded sense of hope and fostering a partnership between patients, our caregivers, and the science that aims to support us. Together, we explore the unknowns, guided by the understanding that breakthroughs begin with a bridge built on hope and inquiry.

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Transcript Summary

  • [0:00 – 2:10] Trial Overview
    The trial, held at Johns Hopkins under the leadership of Drs. Marina Baretti, Nilo Azad, and Mark Yarchoan, is focused on a new therapeutic vaccine approach for cholangiocarcinoma (bile duct cancer). This combination treatment uses checkpoint inhibitors to help the immune system engage more actively with the tumour.
  • [2:11 – 4:30] Vaccination Approach
    The vaccine introduces three specific antigens—CD247, FCGR1A, and TRRAP—to make cancer cells more visible to the immune system. While chosen based on laboratory studies, it’s important to note that these antigens haven’t yet demonstrated patient-proven effectiveness in this cancer type, making the approach largely theoretical at this stage.
  • [4:31 – 6:50] Immunotherapy Context and Checkpoint Inhibitors
    The trial pairs checkpoint inhibitors with the vaccine to potentially enhance immune activation. PD-L1 and PD-1 proteins help regulate immune cell activity, and by inhibiting these checkpoints, the trial aims to give immune cells greater access to tumour sites. Tremelimumab (an anti-CTLA-4 drug) is also included to further promote immune cell activation by reducing early immune system suppression.
  • [6:51 – 8:30] Importance of IDH1 Targeting
    The trial includes a focus on patients with specific genetic profiles, notably those with IDH1 mutations. These mutations are associated with certain tumour behaviours and may influence how the tumour responds to immunotherapy, making them a key focus in identifying eligible participants.
  • [8:31 – 10:00] Challenges of “Cold Tumours”
    Cholangiocarcinoma is considered a “cold” tumour, meaning it produces few immune signals that would typically attract immune cell attention. This cold nature is compared to a “quiet party” that remains unnoticed. The vaccine’s goal is to turn the tumour “hot” by amplifying immune activity around it, akin to starting a louder, more noticeable party.
  • [10:01 – 12:30] Non-Specific Targeting Limitations
    Lipid nanoparticles (LNPs) are used to deliver the vaccine’s mRNA into cells. However, these LNPs do not specifically target only cancer cells; healthy cells may also take up the vaccine, potentially leading to unforeseen side effects and diluting the immune response’s focus.
  • [12:31 – 14:50] Checkpoint Inhibitors and PD-L1/PD-1 Distinctions
    Unlike MSI-high or TMB-high tumours, which naturally attract immune attention, cholangiocarcinoma requires checkpoint inhibitors to assist in immune engagement. PD-L1, PD-1, and CTLA-4 serve as “on/off switches” that can dampen immune response. By blocking these checkpoints, the trial hopes to sustain any initial immune activity triggered by the vaccine.
  • [14:51 – 16:20] Anticipated Challenges and Key Limitations
    Key challenges anticipated in the trial include:

    • The theoretical nature of immune activation, with limited patient data to substantiate efficacy.
    • The non-specific targeting of mRNA, which could impact healthy cells.
    • The low PD-L1 levels in cholangiocarcinoma, which might limit checkpoint inhibitors’ effectiveness.
    • The potential for unknown side effects from the introduced antigens.
  • [16:21 – 18:00] Future Developments
    Dr. Yarchoan mentions future hopes for expanding the antigen targets in subsequent trials. Pending results and additional funding, there may be opportunities to refine the vaccine to enhance immune response in cholangiocarcinoma further.

Trial Details

  • Principal Investigators: Drs. Marina Baretti, Nilo Azad, Mark Yarchoan
  • Institution: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
  • Treatment Structure:
    • Vaccine Delivery: Administered via three intramuscular injections (one in each arm and one in a leg).
    • Checkpoint Inhibitors: Durvalumab and Tremelimumab are administered by IV infusion to sustain immune response.
  • URL for Trial Updates: ClinicalTrials.gov – Not available at the time of writing.

The official title of this trial is Phase 1 Vaccine Trial Using Personalized Neoantigen Peptides for Patients with Cholangiocarcinoma. This pioneering clinical study is being conducted exclusively at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, led by Drs. Marina Baretti, Nilo Azad, and Mark Yarchoan. Sponsored by Johns Hopkins University, the trial is also supported by the National Cancer Institute, bringing together expertise in oncology and cancer immunotherapy.

This trial investigates a unique therapeutic mRNA vaccine approach in combination with two checkpoint inhibitors—one targeting PD-L1 and another targeting CTLA-4—to amplify immune activity against cholangiocarcinoma. By targeting neoantigen mutations common in cholangiocarcinoma, this approach aims to create a recognisable immune “flag” on tumor cells, ideally activating immune responses even in “cold” tumors that usually evade detection. The ultimate goal is to achieve tumor shrinkage and improved progression-free survival rates for participants.

Eligible patients must have previously undergone treatment with gemcitabine, cisplatin, and a PD-1 or PD-L1 checkpoint inhibitor, and their tumors must exhibit specific targetable mutations identified through this trial’s personalized sequencing methods. Every enrolled patient will receive the vaccine and checkpoint inhibitors; there is no placebo group in this study.

To learn more, please refer to detailed resources on this trial available at ClinicalTrials.gov once the full record is live or through the Sidney Kimmel Comprehensive Cancer Center’s site for related updates.

  • ClinicalTrials.gov – Once published, the trial listing will provide official information about the trial objectives, eligibility criteria, and methodology. It’s a primary source for any future patients or professionals seeking the study’s technical details.
  • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center – The center may have published related materials or updates about the trial, possibly in their press releases or research news sections.
  • Cholangiocarcinoma Foundation – They provide ongoing resources for cholangiocarcinoma patients and may offer supportive articles, webinars, or reports about this trial.https://cholangiocarcinoma.org/ (USA)
  • Published Research Articles on Neoantigen Cancer Vaccines – These articles can be valuable for context on how therapeutic cancer vaccines and neoantigen strategies work more broadly. Journals like Nature Medicine, Cancer Immunology Research, and The New England Journal of Medicine often publish relevant studies.

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

    1. 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.
    2. 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.
    3. 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

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