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Key Points
- A 2022 study discovered that M-HIFU physically alters the tumor’s surrounding environment, enhancing the ability of T-cells to effectively destroy cancer cells.
- The study uses mechanical ablation to open up the cells, bypass the immune checkpoint, and make the body more systematically aware of the tumor antigens.
- Combination of ablation therapy and the use of immunotherapy is a real game changer.
- The study’s detailed single-cell analysis offers valuable data.
- The paper the paper is well-composed with good storytelling.
- Future research based on this study might involve investigating the technique's efficacy against dense, solid tumors such as pancreatic cancer.
Background: the battle against breast cancer
Breast cancer remains the most prevalent type of cancer, accounting for almost 13% of all new cancer diagnoses worldwide each year. While advancements in modern medicine have significantly improved patient outcomes and prognoses, researchers continue to work tirelessly to refine cancer treatments to increase their safety, efficacy and accessibility.
A 2022 paper published in Journal for ImmunoTherapy of Cancer, the official journal of the Society for Immunotherapy of Cancer, investigated a potential solution to breast cancer relapse or metastasis after surgical removal.
The paper, titled Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity, focuses on the application of mechanical high-intensity focused ultrasound (M-HIFU) to boost antitumor immune responses.
The researchers discovered that M-HIFU physically alters the tumor’s surrounding environment, enhancing the ability of T-cells to effectively destroy cancer cells. Moreover, when used in tandem with anti-PD-L1, a group of immune checkpoint inhibitors that act as front-line treatment for cancer, M-HIFU facilitates a more robust cancer-fighting response. This coordinated approach aids in curbing tumor growth.
An expert panel delved into the research paper, providing their professional insights. The discussion was moderated by Dr Daniel McGowan, Chief Executive Officer at Cure Parkinson’s NZ and Senior Advisor at Edanz. Joining him in the dialogue were Dr Anthony Swain, Project Manager at Edanz, and Dr Ravi Patel, Assistant Professor of Radiation Oncology at the University of Pittsburgh’s Department of Radiation Oncology.
What is the role of the immune response in cancer treatment and how do tumors evade these responses?
Daniel: Taking a step back and considering how tumors evade immune surveillance is crucial. Our bodies have evolved to detect and attack tumors, but some, like the ones in this study, manage to outrun the immune response.
That's why this study is so exciting. It's not just about the thermal ablation; it's also about seeing CD4 and CD8 positive T cells infiltrating the tumor, triggering an immune response. The gene expression work was also fascinating, showing elevated expression of genes involved in antigen presentation and cytokine receptor interactions.
And, for me, seeing the effect on tumor size was quite impactful. Observing a reduction in the size of the tumor on the non-treated side suggests a robust immune response in action. The study really showcases some promising developments in our understanding of immune responses to cancer.
Ravi: One the hallmarks of cancer, when they published the paper, was that it was able to evade the immune system. We've observed a clear link between immunosuppression and cancer, with higher incidences of tumors during events like the AIDS epidemic. Unique forms of cancer such as Kaposi's sarcoma became more common as people lost their CD4 cells.
The same is true for organ transplant patients who are on immunosuppressants to prevent organ rejection. We often see an increase in cancers, particularly skin cancers and other types typically associated with immunosuppression.
Cancers have a variety of ways to elude the immune system. For instance, they can mask their HLA antigens, effectively making them invisible to the immune system. They can also express immune checkpoints to suppress an immune response. In addition, they can create a hostile metabolic environment; for example, by increasing lactic acid levels and disrupting normal metabolomics, which prevent T cells from surviving in the tumor microenvironment. Furthermore, they could potentially have immune suppressive cells that release suppressive cytokines.
Thankfully, we've made significant progress in the field of immunotherapy, which is now being used to treat a wide variety of cancers. While there's still work to be done in certain areas like breast cancer, the progress in treating melanoma, skin cancers, and renal cancer has been transformative. So, it's safe to say we're making great strides in the fight against cancer.
What novel aspects of this study caught your attention?
Ravi: Triple negative breast cancer is a particularly tough nut to crack, often affecting younger women. What caught my eye about this study is their use of mechanical ablation, which is a little bit different than what is commonly used. Typically, in a clinical setting, when we think of ablation, we consider thermal ablation. In this study, they've used HIFU, an ultrasound-based thermal ablation technique.
However, in practice, we often resort to radio frequency and other types of invasive thermal ablation. The twist in this study was their choice of mechanical disruption (M-HIFU), which doesn't necessarily induce coagulative necrosis from the heat. This is quite a departure from other studies in this field, which made it interesting to me. Plus, it's worth noting how this method can be combined with immunotherapy.
Daniel: Absolutely, the innovation here was a highlight for me. Ablation therapy has been around for a while, and while it does result in cell death via necrosis, tumors often regrow. That's why using mechanical disruption—the shear stress that comes from acoustic cavitation—with HIFU is such a fresh approach.
The standalone results were pretty impressive, but then combining this method with PD-1 therapy, that was a real game changer. They had some remarkable results from that. It’s definitely promising development and could potentially lead to further breakthroughs in cancer treatment.
Anthony: I also found this study quite interesting in general. The idea of HIFU being minimally invasive is fascinating to me. Even though it causes thermal stress and damage through necrosis, it's arguably more invasive than some alternative methods. That's why the mechanical aspect highlighted in this paper seems to be the novel point; it's a slightly gentler application of HIFU, causing what's known as acoustic cavitation.
Instead of just blasting cells open and destroying them through necrosis, this approach seems to encourage a more apoptotic response from the cells. It's a way to open up the cells, bypass the immune checkpoint, and make the body more systematically aware of the tumor antigens. So instead of the traditional brute-force destruction of cells, this method seems to focus more on "waking up" the immune system to the presence of the tumor.
In essence, it's a pretty novel and innovative approach that may change how we view and conduct cancer treatments.
Describe the synergistic interaction between M-HIFU and immune stimuli. How does it compare with other therapeutic modalities?
Ravi: Chemotherapy is frequently used, although it depends on the specific agent as there are many varieties. There are also different targeted therapies. The distinguishing factor with chemotherapy is that it's a systemic therapy, reaching all areas. It's often more suitable for individuals with metastatic disease.
In my own work as a practicing radiation oncologist, my research is in radiation immunotherapy. We frequently use radiation, causing immunogenic cell death in a local area, and then combine it with checkpoint blockade. This is something we're applying clinically, and it's been part of numerous clinical and pre-clinical studies. There's a kind of synergistic effect where the local therapy damages the cells, enhancing the effectiveness of immune checkpoint blockade. It's a similar concept to the study we're discussing, using a local therapy to stimulate an immune response.
Anthony: One of my perspectives on this study is its focus on a more localized approach to stimulate an immune response, rather than starting with a systemic treatment like chemotherapy paired with immune checkpoint inhibitors. Radiation therapy, while effective, can be more invasive and cause more damage to DNA than treatments like thermal ablation or M-HIFU explored in this study.
The paper suggests that M-HIFU can provoke an immune response, increasing the number of dendritic cells in the area and potentially influencing tumor-associated macrophages, thus impacting the tumor microenvironment.
Instead of starting with a systemic response, this approach disrupts the tumor locally before stimulating an immune response that could potentially address other metastatic elements of the tumor systemically. However, it's worth noting that the paper mentions this approach has limited efficacy with larger tumors.
So, if we have a smaller tumor that can be disrupted and then managed systemically by an immune response, this could be a potential strategy for handling any future metastases in a minimally invasive way, potentially sidestepping some of the damage associated with radiotherapy.
Are there any specific limitations that should be addressed as we advance in this field of research?
Anthony: Immune checkpoint inhibitors are really fascinating. They act kind of like an ID badge that a cell uses to signal to immune cells that it belongs, and therefore should not be attacked. One major issue with cancer cells is they've figured out how to appear like normal cells that should be there.
What we need to do is to find ways to expose these oncogenic antigens, the things that differentiate cancer cells from normal cells. This paper we're discussing seems to be zeroing in on a novel version of HIFU. There's been some research done on the use of this treatment for prostate cancer, but it's less prevalent in other types of cancer studies.
It's important to note, though, that this is an animal model study. There's some clinical data supporting the thermal version of HIFU (T-HIFU), but less so for the mechanical version that can help open these cells and increase the number of dendritic cells, thereby stimulating the immune response.
So, this paper seems more like a proof-of-concept than something immediately applicable in the clinic. In essence, it's like a demonstration, suggesting that this is a path worth investigating further and potentially transitioning into more clinical studies.
Ravi: There are a couple of things that are noteworthy in these experiments. First off, the tumor models used, for those of us in pre-clinical animal research, are somewhat immunogenic. They introduced a human HER2 antigen into these models, which can induce an immune response in a mouse. While this doesn't discredit the study, it's crucial to remember these tumors won't behave like human breast cancer tumors.
What we're observing is specific to this cell line and its immunogenicity. Less immunogenic cell lines don't usually show this pattern, at least with other treatments. I don't believe this particular treatment has been examined in that context, so knowing the limitations of animal models is critical in interpreting the results.
Another aspect that piqued my curiosity was the first figure the authors provided in the paper. They compared the outcomes of no treatment, T-HIFU, and M-HIFU treatment alone. Surprisingly, T-HIFU didn't seem to have much of an impact, which was unexpected to me. You'd think that if you heated a tumor to around 60 °C across the entire tumor, there should be a direct effect on the tumor, even if there isn't a distant one, and they didn't demonstrate that.
So, I'm left wondering whether the entire tumor received the therapeutic dose. Their methods mentioned not necessarily treating the whole tumor, which raises questions for me. Even though they were illustrating that the combination treatment is effective, there's a notable difference in the standalone treatments, even without the combination.
Daniel: One of the promising takeaways from these results, as mentioned by Anthony, is the proof of principle that we see—better survival rates, decreased tumor growth, and a stimulated immune response, even in areas away from the treated site. However, the critical next step is to translate these findings to human patients.
What's intriguing about this specific treatment is its non-invasive nature and potentially lower toxicity, especially when compared to systemic treatments like chemotherapy. That said, while we can glean valuable insights from this study, there's a substantial amount of work yet to be done when it comes to bringing this into the clinical realm.
Hopefully, with further research and development, we'll begin to see similar results in humans. But for now, it's essential to proceed with caution and remain vigilant of the challenges in translating animal model outcomes to human patients.
What future investigations could be pursued based on the findings of this study?
Ravi: Designing the right clinical trial is crucial to exploring the potential of this treatment further. One approach we've been using for local therapies involves conducting neoadjuvant studies. In radiation therapy, for instance, we administer radiation and immunotherapy before surgery. This approach allows us to assess the treatment response directly in our patients.
For example, in one of our open trials at my center, we give immunotherapy upfront to skin cancer patients, followed by surgery, which allows us to observe the treatment response. This strategy could be applied to cases like triple-negative breast cancer. You could potentially administer this type of treatment before surgery and then assess the generated immune response when the tumor is removed.
While we're primarily discussing treating larger, visible tumors, there's data suggesting that treatments like this can prevent the development of distant micro-metastatic disease. This capability still has significant clinical value, as generating an immune response could potentially prevent the development of tiny metastases throughout the body.
However, there are limitations to consider. For instance, I believe there may be depth issues with ultrasound and sound waves. A surface tumor in a mouse could differ significantly from a deeper-seated tumor in a human. Therefore, the design of the clinical trial would need to account for the ability to focus the HIFU properly, perhaps by limiting its application to accessible tumors, such as those inside the breast.
Anthony: A concept that intrigued me just a few years back, is the idea of using cancer vaccines. In this approach, you extract immune cells from a patient and stimulate them to produce an immune response against a specific antigen presented on a cancer cell, then inject these cells back to boost the immune response.
Now, using M-HIFU which naturally amplifies the immune response, could potentially enhance the effectiveness of such cancer vaccines. This method provides a minimally invasive way to potentially strengthen other immunotherapies, like cancer vaccines.
I'm not entirely sure how cancer vaccines are combined with other treatments like surgical tumor resection and radiotherapy, but this could open up a potential avenue for bolstering such immunotherapies.
How is the invasiveness of cancer treatments evolving with current advancements in medical technology?
Ravi: Sadly, I don't believe we've ever found a cancer treatment that's entirely free of side effects. This is something I often remind my patients. What's important in any treatment is that the benefits outweigh the costs or risks to our patients. This is a conversation I have with every patient: what are the potential benefits, and what are the potential risks?
We aim to ensure that the benefit window remains high while keeping the risk as low as possible. The level of risk we're willing to take varies, of course. We're more likely to take on more risk when we believe we can cure a patient's cancer, and less when we're merely attempting to alleviate some symptoms.
I have my doubts about whether even mechanical shearing has zero side effects. It can be hard to detect side effects in mice, given that they can't express discomfort or complaints. Even if I irradiate a mouse tumor, most side effects may not be apparent simply because the mouse can't communicate its discomfort.
However, as mentioned previously this mechanical approach does seem to have the potential for less toxicity. There likely will still be some, but possibly less than with thermal ablation. I'd be interested to see how it compares to radiation. Radiation does cause DNA damage, but I suspect that this mechanical stimulation also kills cells. We see this from the treatment alone, even without adding checkpoint inhibitors. So it probably also affects some normal tissue cells through shearing. The exact extent of this and how well it can be controlled, I'm not certain based on this study.
Still, we definitely need new treatment options, and local therapies have a significant role to play. Systemic therapies are sometimes much harder to tolerate, especially when we're talking about cytotoxic chemotherapy.
Anthony: I think calling any of these therapies "non-invasive" might be a bit too optimistic. Any treatment we're talking about is going to cause some kind of disruption. To be honest, I can't think of any therapy that is completely non-invasive. Even something as simple as taking a paracetamol for a headache involves some level of trade-off. The paracetamol itself could potentially cause liver damage in certain situations. So, no matter what, there's always going to be some level of intervention when it comes to treatments.
I think a key goal of this study was to introduce M-HIFU as a less invasive alternative to T-HIFU. But describing it as non-invasive might be stretching it a bit. And we must remember, all of this is based on a mouse model. It's one of the significant hurdles we face. Without clinical data, it's hard to comment on how this will translate to humans. As Dr. Patel mentioned, mice can't voice their discomfort, so there are limitations to what we can learn from them.
Any thoughts on the overall presentation of the paper and what recommendations could you provide for researchers aiming to publish their work in high-impact journals?
Ravi: The rigor of the science is key when I review a paper. This includes using multiple tumor models, particularly for higher impact journals, which was done here. Replicability is crucial, too. Sometimes, immune studies in mouse models yield results once but fail to do so the second time, so I appreciate seeing multiple replicates. For statistical power and reproducibility, it's beneficial to run two replicates.
Another positive aspect of this study was the detailed single cell analysis, and their comprehensive techniques offer valuable data. However, I'd advise not to skip controls as it might invite questions from reviewers.
Lastly, when publishing in high impact journals, consider the reviewers' comments as constructive. If they suggest more studies, it might be worthwhile to carry them out, unless it's an impractical request like for example running a new clinical trial. This process will strengthen your data and present a more rigorous and robust research paper. I experienced this with my postdoc paper, where an additional year of studies significantly improved the final product.
Anthony: Most of my work focuses on clinical trials, so a non-clinical trial like this requires a meticulously detailed methodology section. This paper delivered on that, outlining aspects like flow cytometry and single-cell RNA analysis thoroughly.
The authors also effectively leveraged supplementary materials to share an abundance of data. Even if it didn't make it into the main paper, the extensive online supplementary material is a great asset.
One minor critique I have is regarding the title. Although it didn't prevent the paper's publication, specifying that this was a breast cancer model might have attracted a more targeted readership.
Otherwise, the paper is great and well-composed. The story-telling aspect is commendable. My only other suggestion pertains to minor visual elements, such as using the same symbol in each graph when presenting the non-treatment, T-HIFU, and M-HIFU data. These suggestions are admittedly nit-picky, but overall, it's a strong piece of work.
Daniel: This paper is undoubtedly comprehensive, containing a wealth of figures, including many supplementary ones. However, given the complexity of the results, I feel a schematic or a graphical abstract to summarize the story would have been beneficial. It could help distill the findings into a single, digestible image, a feature increasingly used for scientific communication in many journals.
While the lack of such a visual summary is a minor omission, it doesn't take away from the overall quality of the paper. I found it to be thoroughly conducted and a genuinely impressive piece of work.
The Bottom Line
In essence, the paper provided crucial insights into the fight against breast cancer using M-HIFU. In the panel discussion, Dr McGowan, Dr Swain and Dr Patel dissected the novelty of the study, emphasizing its exciting results. The panel also identified some limitations within the research and suggested potential avenues for future research. Additionally, the trio also evaluated the effectiveness of the paper’s presentation and proposed strategies for securing publication in high-impact journals.
The panelists collectively voiced their anticipation to see how this study progresses, especially in terms of its application in future clinical trials. While its potential implications primarily center around breast cancer, the approach could feasibly extend to other types of cancer. A promising direction for future research might involve investigating this technique's efficacy against dense, solid tumors such as pancreatic cancer.
About JITC
Journal for ImmunoTherapy of Cancer is a premier publication that serves as a global hub for the latest discoveries, expert insights, and multidisciplinary collaborations that are revolutionizing cancer treatment. The journal showcases a diverse array of articles, peer-reviewed by leading experts, offering a comprehensive exploration of the most promising approaches in immuno-oncology. From groundbreaking clinical trials to novel therapeutic strategies, the journal features the pivotal studies that shape the future of cancer care. It is the official journal of the Society for Immunotherapy of Cancer and published in partnership with BMJ.
Breaking New Frontiers in Scientific Publishing: The Dynamic Collaboration of BMJ and Edanz
With a shared commitment to excellence, BMJ and Edanz have forged a union that leverages their unique strengths. BMJ's unparalleled reputation as a leading global publisher, known for its rigorous peer-review process and high-impact journals, merges seamlessly with Edanz's deep domain knowledge in scientific editing and author support services.
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