Team:ETH Zurich/HP/Gold Integrated
Perspectives on our Project
Throughout the design and development process of CATE, we consulted different experts in fields ranging from MRI to bacterial cancer therapy. With their expertise we were able to adapt CATE and create a solution is that safe and tackles core issues. Click on the pictures below to read the interviews.
Interview with Dr. Simon J. Ittig
To fully understand the capabilities of bacterial cancer therapy and to develop a better method, we reached out to T3 Pharmaceuticals. T3 Pharmaceuticals was founded as a spin-off of University of Basel in 2015 with the goal to improve the lives of cancer patients by developing therapies based on live bacteria expressing the Type III Secretion System (T3SS). Despite their busy schedule, CEO and co-Founder Simon Ittig agreed to meet us in the Biozentrum, Basel.
Interview with Prof. Markus Rudin and Dr. Aileen Schröter
Magnetic resonance imaging (MRI) is a powerful non-invasive technique to visualize soft tissues including tumors. Its superior spatial resolution and the absence of radiation burden have rendered it a prominent imaging method in healthcare and biomedical research. We had the great opportunity to meet Prof. Dr. Markus Rudin, head of the Functional and Molecular Imaging group at the Institute of Biomedical Engineering at ETH Zurich and Dr. Aileen Schröter who gave us valuable insights into the world of MRI experiments.
Interview with Dr. Christian Britschgi
As a part of our research about what the experts from various disciplines think about our project, we decided to reach out to Dr. Christian Britschgi, an oncologist working at the University Hospital in Zurich. Doctor Britschgi deals with novel treatments on a daily basis as the director of the Phase 1 Unit at the Department of Oncology. He was generous to share his opinion on current treatment options in cancer therapies as well as his thoughts on our project. Thanks to his inputs, we were able to see the advantages and disadvantages of our system more clearly and apply what we have learned into the planning and engineering of our project.
Interview with Dr. Sacha Rothschild
In order to learn more about the current state of cancer treatment we reached out to Dr. Sacha Rothschild of the University Hospital Basel. Due to his background in basic science, translational medicine as well as the clinical setting we were able to learn about the whole spectrum of current and future cancer treatments from him. He further gave us inputs on how parts of our system might be applied and what to consider when developing such an approach.
Our Project in the Context of Bioethics as Seen by Prof. Darko Polšek
To put our project in the context of medical ethics, we reached out to an expert in sociology, philosophy and bioethics, professor Darko Polšek from the School of Human and Social Sciences at the University of Zagreb. He was kind to share his opinion with us in a letter and to point out ethical issues and controversies we might face as we develop our project.
Why bacterial cancer therapy? Does this have a future?
There are lovers and haters. Some people say that bugs are not drugs and some companies focus entirely on small molecules. For them you’re not a good partner. I do believe that the technology is well advanced and robust. We have a lot of data to demonstrate this and it inspires confidence in people. Importantly, we also have confidence in our capabilities. I think treating something chronic and non-lethal with this system is going to be difficult due to regulatory barriers. You need a case where you know that the medical need is so high that you can dare to treat the patients with something more exotic. Importantly, the clinician must trust in the treatment in order to administer it. There are two US companies working with Listeria in the clinics who received allowance for clinical trials by the FDA and EMEA. This shows that it’s not a no-go. One can do it. People have seen the hurdles already. Of course, there are people who are rather conservative and some that are very open-minded towards such new assays. But in general, there are enough people who support bacterial cancer therapy.
In Switzerland GMOs are rather controversial, do you encounter any problems?
No. I think people just don’t want to eat it. This need is not there in Switzerland because there’s enough food for everyone and people can exclude any minimal risk that might exist by simply not consuming it. But people that suffer from advanced stages of cancer are a very different case. In comparison to other treatment options, the potential side-effects are so minimal that one is willing to take risks. From this perspective, GMOs weren’t met with a lot of resistance.
When will bacterial cancer therapy become reality? How far is T3 Pharma?
Let’s say we’ll try to make it until 2020. There are US companies like Aduro that have entered phase II clinical trials.
Do you benefit from bacterial systems getting approved?
Yes. There’s for example BCG, Bacillus Calmette-Guérin, which is approved to treat bladder cancer and is actually administered in Switzerland. When you talk to urologists you’ll realize that they know it quite well. So in principle, all of this already exists which is very helpful. From this perspective I don’t see other companies as competition at all. The modes of action are very diverse and it’s good when people can see that these methods are not made out of thin air.
We had similar experiences. When we told people what we’re doing and then mentioned that this form of therapy is not new, that studies exist etc. then everyone was okay with it.
I think the biggest sceptics are academics and not drug developers. Clinicians almost always gave us positive feedback. Regulatory experts, drug developers – they see the medical need and what was already developed. Academics are more likely to say: “It will never happen.” But that’s not tragic. I think it helps me is that during my PhD I concerned myself with LPS [lipopolysaccharide] and sepsis which gave me good fundamentals for arguments but I can also understand the skepticism to a certain degree.
I do believe that the technology is well advanced and robust. We have a lot of data to demonstrate this and it inspires confidence in people.
Indeed, injecting bacteria sounds rather adventurous.
Yes, certainly. It offers some interesting benefits though. What’s not intuitive for many people is the fact that the compound proliferates. You end up with more of the compound than you injected initially – that’s very different from classical drugs. Also, compared to synthetic small molecules, your body has evolved to cope with bacterial infections. You shouldn’t underestimate this. Because of this, intravenous administration of bacteria brings about a huge selective pressure. If you design your system in such a way that there’s any chance for the bacteria to get rid of it, it will be gone. At the same time, the bacteria still have to reach their target.
Have you observed different efficiencies between different cancer cell lines? Are you focusing on a specific type of cancer?
Not yet. We’re trying to keep all options relatively open but of course we’re screening different cancer cell lines. In principle, the T3SS is quite promiscuous. The difficulty is rather that our system could work for many things.
The system we’re trying to build would be controllable and should minimize side-effects. Do you see opportunities to improve it?
Is azurin active in the membrane? Many toxins that are active in the membrane are also active in bacteria.
No, according to the literature not.
Good. You see, the tumors we work with are incredibly efficient growth machines. You can do all kinds of things in these cell cultures. A few cells might remain and the next day the plate is covered again. For an approach like yours, I’d choose a toxin that has an extremely strong effect. Something that acts in a "hit and run" manner ---you administer it once and then it acts by itself. Maybe something which induces apoptosis. Once you flip the switch it wouldn’t matter whether the initial stimulus is still there or not. But if you bring the tumor only into a small imbalance where not all the cells are "flipped" you run into problems of resistance.
Yes, we fear that if the toxin is not potent enough that the cancer will become resistant.
The way I see it is that you’re building a toolbox where components can be replaced. It’s important that you guys keep in mind that you can replace it with something else. Usually, the primary tumor is not the main problem but the metastases. So as an alternative, you could think about an approach employing the immune system. There are cytokines that can be produced by bacteria such as IL-2, which is approved for certain kinds of metastatic cancers. The idea is to administer it into the tumor which causes the immune system to sweep in, fight off the tumor and build a memory. This memory will allow the immune system to also kill the metastases. But of course there are also cases in which the primary tumor is the main problem. There your approach to deliver a toxin makes sense. The question remains for which kind and size of tumors it works. A tumor needs to have a certain size in order to have sufficient blood flow toward it that brings enough bacteria to form a colony there.
The way I see it is that you’re building a toolbox where components can be replaced.
We are also planning to incorporate an imaging module that would allow a clinician to see colonies of the bacteria.
I really like the idea. In clinics it was a problem that the colonization by Salmonella didn’t really work and it’s extremely difficult to track and study the bacteria in patients. With biopsies one can only look at a specific spot. When the bacteria are not there, one would conclude that there was no bacterial colonization. When they excised the whole tumors though, they usually found bacteria which they couldn’t detect with the biopsy.
But even if we would wait for several of days, could there be a homogenous colonization of the tumor?
Well, I believe since the tumor itself is intrinsically heterogeneous it is unrealistic to assume that this can be achieved. And then there’s the question of how the bacteria behave. Do they remain single cells? Will they form little colonies? Probably every strain behaves differently. So it would be very difficult to achieve a homogenous distribution.
And finally, do you have any pitching tips? What makes you so successful?
[Laughs] I wouldn’t have described us like that. There are some people who present their projects similar to road-shows and the claims are not really based on science anymore. I myself am extremely uncomfortable with presenting conclusions that are not backed by solid data. This can be difficult since you won’t get far with sceptic statements so you have to make some bold statements. But still, there's a wide spectrum between this and "I’m Michael Jordan, woah!". In the end I think it’s really important that you’re authentic, that you believe in what you present and that you’re comfortable with it. Of course, pitches and talks will be much better when you practice a lot in advance. When you do that, everything sits perfectly but you’ll also be able to address questions and can to adapt to circumstances. If you feel comfortable during your presentation you might even start enjoying the process.
Thank you very much for your time and your inputs.
You’re welcome.
Disclaimer: This article contains excerpts from the interview that were translated from German and is not a full-length word-by-word transcript.
How long does it currently take it to image a tissue? Is this something that could restrict application in the clinics?
If you have typical contrast agent concentrations, we’re speaking of minutes. Of course, an important factor is how fast the contrast agent builds up ---that’s physiology. But the actual imaging time is certainly not a limiting factor. Unless you’d like to achieve microscopic resolution. Do you have any information on how these bacteria behave within the tumors? Do they colonize just the surface or do they penetrate deep into the tissue?
They populate the border between necrotic and living zones of the tumor. Thus, a thin bacterial layer of about 0.5 mm width in the middle of the tumor is formed. This is how we model it based on papers we’ve found.
In that case there are two issues you have to be aware of. First, 0.5 mm is certainly within our resolution limit, at least in mice. In humans that might be more challenging though. Second, imaging iron contrast agents, as you plan to use, with typical MR sequences leads to something that is called the “blooming effect”. Due to that you will see phase distortion much beyond the actual dimension of the bacteria. This is good on the one hand since it facilitates detection but on the other hand it’s also bad because it makes it more difficult to determine the accurate location of the bacteria. Of course, one can correct for this blooming effect with modeling. To circumvent the issue, one can also use other sequences that are less sensitive towards contrast but more accurate regarding spatial localization. But I think in your case the benefits of the blooming effect outweigh the drawbacks. What ultimate read-out do you envision for assessment of efficacy of your treatment? Tumor volume?
Yes, if the toxin is killing a sufficient amount of cells, we’d probably observe some collapse of the tumor that would be represented in volume.
There’s a huge variety of read-outs with which one can assess efficacy. You could also go for a metabolism-based read-out using additional imaging technologies. PET [positron emission tomography] for instance. There, the use of FDG [Fludeoxyglucose (18 F), a constrast agent for PET] is very common to assess efficacy. That way, you could observe proliferation rates and other read-outs reflected in metabolism. In clinical settings, PET to read out tumor volume is probably the most common method. In general, there’s different assays to measure efficacy that you can take into consideration. Probably, mouse survival rates would have been the easiest one. The interesting part to me is how specificity for tumor tissue is achieved. Your basic assumption is that the bacteria home in, or better phrased, survive in tumor tissues and not others. What would happen if there’s an inflammation?
Our emergency break are antibiotics. One could encode kill switches but as far as we know, they’re not reliable enough yet. This is why we’d administer antibiotics in case of any adverse symptoms to get rid of the bacteria.
And you assume that the immune system of a cancer patient would be strong enough to kill all the off-target bacteria?
Our system is not going to replace standard treatments like chemotherapy of course. It’s rather a supplementary treatment modality. For late-stage cancers our system wouldn’t be potent enough and for very early stages it also wouldn’t work. It’s a solution that would be applied somewhere in the intermediary stages of cancer where the immune system should still be active enough. Still, that’s definitively something to bear in mind.
The good thing is that you have potential corrective measures such as antibiotics as you’ve said. As long as you have those you’re on the safe side.
You could also go for a metabolism-based read-out using additional imaging technologies.
Another problem would be for example the stability of our system but the solution to this lies probably more on the SynBio side rather than imaging. Do you see other potential drawbacks?
The project in itself is really interesting but I’m not a tumor expert. There are many new approaches in the field of oncology and this is also certainly an attractive one. Interesting features are the specificity and the ability to switch your system on and off by changing certain physical parameters. These are aspects which make it really attractive. Even if you have off-target effects you can still take action and switch it on and off. From an imaging perspective, a difficulty could be to differentiate between blood vessels and bacteria. In the blood, the oxygenated hemoglobin affects your contrast, deoxyhemoglobin does not. It may become one of the challenges to distinguish your bacterial population from vessels.
Except we would overcome the signal-noise ratio by overexpressing enough of the contrast agent.
Yes, you may have a sensitivity advantage. Or you could do a so-called oxygen challenge. The patient or mouse is given oxygen to better oxygenate the blood. Thus, there’s more oxyhemoglobin in the blood and the signal from the vessels would decrease. So there are tricks. But keep in mind that every iron in your system can generate signals and may confound your bacterial signal. Additionally, calcification in the tumor may also result in contrast signals. But in any case should could take a baseline image and then image again after administration of the bacteria. The resulting difference by itself might already settle many issues.
So in general, do you think our system is realistic?
Based on the numbers you’ve presented it’s realistic to have enough sensitivity. For sure in a test vial. For in vivo conditions one would have to see. If there’s a very strong contrast in test vials then it’s also realistic for in vivo conditions.
We were also thinking about imaging 3D structures such as stacks of cell layers after triggering the bacteria in a single spot.
What’s often used are tumor spheroids which are basically tumor cells growing in a sphere. This way you obtain 3D information which is relevant for many aspects. It’s an established technique. So this might be an option. But it’s more often used in microscopy rather than MRI because typically the dimensions are small. Too small for MRI in many cases.
So we would have to replace MRI with fluorescence microscopy in this case?
Yes, for example. But let’s say you have your vial with bacteria and you trigger one specific spot, that would be certainly something we could track.
Based on the numbers you’ve presented it’s realistic to have enough sensitivity.
Are you aware of any other genetically encoded contrast agents that might be better than bacterioferritin?
Iron is certainly attractive because it has a great magnetic spin.
We were also looking at CEST [chemical exchange saturation transfer] MRI. What’s your opinion on this method?
Iron is definitely more sensitive. The technique is attractive because you can encode it on a computer and you don’t need any substrates like iron to activate it. But consider that the iron effect is much stronger than the CEST effect. Sensitivity is not its strength in most cases. And if you’re not sure about which local concentrations you’re going to reach in the tumor then rather go for higher sensitivity read-outs such as iron. Also, complexed iron such as ferritin is very well tolerated by cells. An alternative would be to use non-MR techniques. For some of the experiments you could consider microscopy but then the translation to clinics would be more difficult. For clinical settings, PET would be another option as there are many PET reporters like thymidine kinase.
We were also looking into PET. The contrast agent production in bacteria could be catalyzed by thymidine kinase. But with PET you would require ionizing radiation.
You’d also need radiochemistry to provide you with the substrates for the enzymes. From this point of view, it’s more resource-intensive than the MR approach.
Thank you for your time and inputs!
You’re welcome.
Disclaimer: These are excerpts from a longer interview with Prof. Rudin and Dr. Schröter and have been edited for brevity and clarity.
What is your area of expertise?
At the oncology department, we are organized in such a way that each senior physician takes care of a specific disease entity. My specialties are lung and thoracic cancers and sarcomas. Additionally, I direct the Phase 1 Unit, which is the early clinical trials unit, certified by the Swiss Group for Clinical Cancer Research. This is a transversal platform and therefore deals with testing new drugs for a diverse group of tumor entities. Lastly, I am responsible for the Molecular Tumor Board together with Prof. Wild, Institue of Pathology, which includes weekly meetings to discuss the results of genomic profiling of patients for diagnostic purposes. Comprehensive genomic profiling on biopsy samples is being done more and more and at our meetings we discuss the implications that these results have on the treatment of the patients.
Apparently you deal with both conventional treatment options and modern therapies in clinical trials. In your everyday practice, what is actually mostly used? Is it still chemo- and radiotherapy?
Radiotherapy is performed at the Department of Radio-Oncology, so this is not a treatment a Medical Oncologist is involved in. In Medical Oncology, we use systemic therapies to treat patients with cancer-chemotherapy, targeted therapies or immune-therapy. If you look at the absolute numbers, classical cytotoxic chemotherapy is by far the most used. However, more and more, we also use immunotherapy, specifically monoclonal antibodies that work as immune checkpoint inhibitors. However, in most cases these are not first-line treatment options, but rather a type of treatment that you will use in patients with metastatic cancers that have not responded well to chemotherapy. The third type of treatment we use is the targeted therapy, when possible. For targeted therapy, genomic profiling must first be done and only if a certain mutation that actually can be targeted is present, the use of this type of treatments makes sense.
If you look at the absolute numbers, classical cytotoxic chemotherapy is by far the most used.
In the media, we have lately been hearing a lot about these modern treatment options, such as immunotherapy and targeted therapy. They seem to be very promising. Do you see these modern therapies completely taking over the classical approaches or do you think chemotherapy and radiotherapy will not be replaceable in the near future?
The problem with these modern treatments is that the groups of patients that are eligible are becoming smaller and smaller as the therapies become more advanced and specific. For example, in a group of lung cancer patients, the most common mutation that we know of is a KRAS mutation and there are no KRAS-inhibitors available at the moment. Additionally, a big percentage of patients has mutations that we don't even test for simply because we are not yet familiar with all the possible driver mutations for cancer and therefore have no drugs targeting these genes. Actually, only a small percentage will have a mutation suitable for targeted therapy. This therapy will then typically work very well in the beginning, but at some point, the tumor will mutate further and become resistant. At this point, you might be able to target yet another mutation with a different therapeutic agent. But again, after a while the patient will typically lose the mutations that we can actually target. Once this happens, we are left with chemotherapy as our only option, since we are out of targets.
What about CAR-T cells? They have been getting a lot of attention recently.
In hematology, there are many ongoing trials at the moment. In our department, we also have one trial ongoing for treating mesothelioma [an aggressive cancer that develops in the lining of the lungs]. The antigen that we target is located on the surface of mesothelioma cells and after engineering the T-cells, we inject them into the pleural space [a thin space between the two membranes covering the lung]. At the moment, it is hard to predict how well this therapy will work since phase 1 trials are designed to test for the tolerability of an approach. In general, CAR-T cells are on the market for leukemia already, so there is definitely promise for this therapy. However, the risk of toxicity is high-engineered cells can also attack something that they should not. Additionally, the process of harvesting, engineering and returning the cells is time-consuming and expensive. It is a therapy tailored to each and every single patient, which makes the process more complicated.
In our project, we deal with an atypical approach to treating cancer. We're working with live bacteria engineered to deliver a cytotoxic drug to the tumor. Although not well known, the concept of using live bacteria administered intravenously to treat solid cancers is not actually new. Have you ever come across this approach during you career?
Bacillus Calmete-Guering is used to treat localized bladder cancer. However, this is the first time I came across a systemic use of live bacteria to treat cancer.
I would say that the step that includes the activation of the bacteria once they have accumulated in the tumor with focused ultrasound is open to discussion.
What are you thoughts about our project? What do you see as the biggest advantage? What about disadvantages?
I think it's a very interesting approach. I would say that the step that includes the activation of the bacteria once they have accumulated in the tumor with focused ultrasound is open to discussion. On the one hand, it is good to have an additional control step prior to release of the toxin, but on the other hand your effect is limited to the place where you apply the ultrasound pulse, so you will not treat micro-metastases that you cannot see. This makes your approach somewhat more local than systemic, while without the additional temperature controlled step, you would have a targeted systemic treatment, which would be very appealing. Of course, the ability to treat the primary tumor and metastases simultaneously is also very attractive. In this case, you would still need to apply a conventional systemic treatment to treat micro-metastases.
What about the idea of giving bacteria intravenously in general? How does this sound to a clinician?
[Laughs] That's a good question. You are dealing with a non-pathogenic strain and if it is properly tested pre-clinically and in early trials, I think there is not much to discuss there. Like with any other treatment, if it works and is tolerable, it can go on to further stage clinical trials.
So if there was a clinical trial involving bacteria to treat cancer, would you take part?
Yes, of course. In our Phase 1 Unit we deal with novel treatment approaches and we are always interested in new ideas. The fact that you would use bacteria intravenously would not be an exclusion criterion, if it has passed all the required pre-clinical tests, of course.
Given your experience with introducing patients to new treatments, do you imagine they would have a problem with the idea of administration of genetically engineered bacteria to them?
No, not at all. Cancer patients are very open to new treatment approaches. Most of the patients react very positively if we inform them well about the safety and efficacy of a certain treatment, or about the pros and cons of a novel approach. Although it is true that there is always controversy when discussing for example genetically modified plants, I think that people can differentiate between these topics and I don't see the fact that your bacteria contain artificial genes as a potential problem. Moreover, if you look at the CAR-T cells, these are also genetically engineered cells, but patients don't seem to mind much. Another advantage of your system in this context is the fact that the bacteria do not have to be engineered specifically for every single patient, as is the case with CAR-T cells.
The fact that you would use bacteria intravenously would not be an exclusion criterion, if it has passed all the required pre-clinical tests, of course.
Another potential issue related to our approach is the fact that the patient would have to remain still for a couple of hours during the treatment, as this might be necessary to activate the thermo-sensing system with the focused ultrasound. Do you see this as a big disadvantage?
It might be a disadvantage, but in general, this shouldn't be a big problem.
Disclaimer: This article contains excerpts from a longer interview and has been edited for brevity and clarity.
What is your area of expertise?
I’m a medical oncologist dealing mainly with thoracic and lung cancers. My second focus are patients with neck and head cancers. But since our hospital is not too big, in my daily work I treat patients with all kinds of solid tumors. Furthermore, I obtained a PhD from the University of Bern working in a basic research lab at the department of clinical research. The focus of my research was to further investigate the role of the Src tyrosine kinase and its downstream targets in lung cancer. I was able to describe two microRNAs conferring resistance to Src tyrosine kinase inhibitors. Here at the University Hospital I continued doing research but with a focus on clinical trials in cancer immunotherapy and also some targeted agents. Additionally, I’m a project leader in the lab of Professor Zippelius who has a strong focus on cancer immunotherapy.
So it seems you have a really broad perspective both on the basic science as well as the clinical every-day work with patients. When it comes to treating patients, which treatment modalities are used most often?
For the largest part of patients it’s still chemotherapy but more and more patients nowadays are treated with immunotherapy. We now have different agents that are approved and have already become standard of care for different tumor types. Moreover, we run a lot of clinical trials with immunotherapeutic agents for different kinds of cancers. There are also more and more targeted therapies available. We are also starting to combine these different therapies, at least in clinical trials.
In your opinion, do you see chemo- or radiotherapy becoming obsolote in the near future?
No, I wouldn’t say obsolete. The landscape is really changing though. The first immune checkpoint inhibitor became available around 5 years ago and now we already have it for different kinds of tumors. Therefore, this marked a new era in cancer therapy. But still, we cannot cure most patients with advanced/metastatic cancer. So what we do now is that we start to combine these classical treatments you mentioned with the newer agents. As such, there is definitively a role for chemotherapy in the future. Even more so for radiotherapy which has been shown to improve tumor response to immunotherapy by inducing an immune response itself.
So do you see mainly immunotherapies becoming more and more important?
Yes, I think so. Probably not in all tumors though because there are many tumors that are not responsive to this kind of treatment. Take breast cancer for example, the most common form of cancer in women. So far it is not very responsive to the immunotherapeutic agents we are able to use nowadays. On the other hand, there are kinds of cancer, such as malignant melanoma, where the introduction of immunotherapy really changed the prognosis from really bad to quite good.
What about the response rates to, for example, checkpoint inhibitors? To our knowledge this is an issue that is still limiting the applicability of many new forms of treatment.
If you look over the whole range of tumors you might have a response rate of approximately 25 to 30 percent. Then there’s another 30 percent of patients that show a disease stabilization which is still something. But then there are still around one third of patients that have absolutely no benefit from these agents. If you compare these numbers to chemotherapy in metastatic disease where you have around half of the patients not responding to the classical treatment, there is hope. So for the future what we need is that we become better at selecting patients using predictive markers. We do have some ideas what markers to use but they’re not very reliable yet. Therefore around 30 percent of the patients we treat with these agents still just don’t respond.
There are kinds of cancer, such as malignant melanoma, where the introduction of immunotherapy changed the prognosis from really bad to quite good.
Is this also an issue you face when you apply targeted therapies?
No. There we have the advantage that it’s, well, targeted. We know in advance that the patient has a certain mutation that we can target. Take for example again lung cancer. We know that around 10-15 percent of patients harbor an EGFR mutation for which we have targeted agents. If a patient has an EGFR mutation and we use the targeted approach, around 75 to 80 percent of patients will respond. There is, however, the problem of resistances. After around a year the tumor will grow again. We now try to understand the molecular mechanisms of resistance in detail and develop new agents that target the resistance mechanism. Additionally, usually only a subset of patients actually harbor a mutation that is targeted in the first place.
Have you ever heard of bacterial cancer therapy?
Only from a research point of view and BCG for early urological cancers which is routinely used in clinics.
In our system, there would be the option for the doctor to confirm the localisation of the bacteria via MRI. Would you use it?
Well, this would be an extra step in the procedure that we usually would not do because before you administer your treatment you would have already performed all the imaging steps. So in the clinics we wouldn’t need another imaging step to confirm the location of the bacteria. Also, MRI is expensive to do and causes stress for the patient. So I think we wouldn’t actually apply the imaging step. Another thing: how long does it take the bacteria to colonize the tumor upon injection?
In mice, it was shown that after 3 to 4 days after injection, the bacteria are exclusively found in tumors.
That’s good then. And what about the immune system? Are your bacteria not recognized and killed?
Yes, they are. And most of them will be killed by the immune system but survive in tumors where the immune system is downregulated. So it comes down to the right balance between having enough bacteria to reach and start a colony and avoiding sepsis.
So in the context of immunotherapy your system might run into a problem then. The general aim of these new treatments is to overcome the immunosuppression which might interfere with your assay. So it would be problematic to use your assay with or after immunotherapy.
In the clinics we wouldn’t need another imaging step to confirm the location of the bacteria. Also, MRI is expensive to do and causes stress for the patient. So I think we wouldn’t actually apply the imaging step.
Another checkpoint in our system is the focused ultrasound. This step would require patients to lie still for a couple of hours. In your experience, do you think that would be a problem?
Might be. Some patients are in pain and this could be too much. But then again, many patients have to be here for 3 to 5 hours to receive chemotherapy intravenously. What about the side-effects though? Would focused ultrasound be painful on the skin for example?
No, the ultrasound comes from different sides and only where the beams come together, heat would be created.
That’s okay then. And what about depth? Are there any limitations on the location of tumors you could reach?
The depth is not really a problem. What could be problematic are the lungs since they are filled with air that interferes with ultrasound propagation. And what do you think about our choice of toxin? Do you think we should choose something more potent or rather be more cautious?
You should certainly not overdo it. An interesting aspect would be if you could bring targeted or chemotherapeutic agents to the tumor site. Then it would be somewhat similar to antibody-drug conjugates where you also bring a chemotherapeutic agent preferentially to the tumor site. I think if you were able to that, this would be interesting.
In case our system would be shown to work well in preclinical studies, would you consider taking part in a clinical trial featuring such an approach?
Yes, if it has a convincing phase I trial design and reasonable preclinical results. The idea itself looks interesting, and if I would have been provided all the detailed results and toxicity studies, sure.
Do you think patients could be reluctant to try out such an approach?
An interesting aspect would be if you could bring targeted or chemotherapeutic agents to the tumor site.
That always depends on how you explain it to patients. In my experience, when you first approach patients about chemotherapy, most of them are reluctant and afraid of toxicity and side effects. But after thorough explanations most of them agree. I assume it would be the same for your system.
What about the fact that we genetically engineer bacteria? A lot of people are opposing genetic engineering in Switzerland.
No, at the end of the day it is a question of toxicity and patient benefit. If you have sufficient preclinical data showing that it works, we can explain it. Still, there’s always less open-minded patients that would not be willing to participate, but that’s not restricted to your approach.
In your opinion, what do you like about our approach? And where do you think we could improve it?
Certainly, the attractive thing is that it is focused on the tumor and should, hopefully, not exert its effects outside the tumor. The disadvantage is the fact that you use bacteria. We have absolutely no experience with injecting bacteria into the bloodstream. It’s then of course also a question of how to handle the bacteria which is probably more difficult than small molecules or proteins only.
Thank you very much for your inputs and your time!
You’re welcome.
Disclaimer: This article contains excerpts from the interview and is not a full-length word-by-word transcript.
Head of the Anthropology Study Group
School of Human and Social Sciences (Philosophical Faculty)
University of Zagreb
I. Lučića 3
10000 Zagreb
Croatia
To: Whomever it may concern
Zagreb, October 26, 2017
Dear Ms Telarović,
Thank you for your concern. I wish you and your collaborators all the best in establishing a viable method for treating tumors. As you know, my field of expertise is not medicine, but rather social and human sciences, so I would not dare interfere (justify or criticize) in anything remotely connected with medicine proper, nor with the contents of laboratory procedures you are about to embark on during your investigation.
Your project is very ambitious, especially as a student project, and I endorse it wholeheartedly for its ambitiousness.
As far as I can tell, though, from afar, from the bioethical point of view, since you asked there are a couple of points I may raise. Your project is very ambitious, especially as a student project, and I endorse it wholeheartedly for its ambitiousness.
The second point concerns the safety of the procedure. As far as I can tell, you and your collaborators are going to treat tumors (in patients in vivo? --- from the poster you sent me it is not discernible) with non-pathogenic E. coli strain. I hope you will assure your sponsors and evaluators that it is indeed non-pathogenic, namely that there would be no prima facie harmful side-effects from the treatment.
Thirdly, while getting an informed consent from your patients, I hope you would not dare to get the permission from the patients only from the fact that they might be desperate. Despair is not the viable justification for granting a judicious informed consent. What this means, in short, is: you should not rely on their despair only. And if you by any chance did, I hope you explained them extensively both the merits of entering and of not entering the procedure. Also, concerning the other bioethical principles, I hope you and your collaborators assessed the costs and benefits of the procedure in terms of doing no harm, or else, doing something beneficial, and compared the potential harms of the procedure with the potential harms of doing nothing.
Despair is not the viable justification for granting a judicious informed consent.
The point above, about assessing the harms/merits of action (starting a procedure) and inaction, should be reiterated. According to several legal documents (most notably Helsinki declaration), while assessing the possible merits and harms of your procedure, you should take into account the so called "golden standard" of comparison. This means that the outcome of your bioethical tally should properly account for the best possible alternative from non-intervention. You should compare the outcome of your action (project, procedure) with the outcome of administrating the best possible/known alternative treatment for the same disease. This is a rather high call, especially for a student project, but nevertheless, it is useful, and introduced into legal documents with good grounds.
In spite of the fact that you may treat these precautionary notes as a nuisance, as claims of an all-too-high- an-order, you should nevertheless take them into account.
While administering your treatment you should rely on two research safeguards, not visible from your poster: The first one concerns creating two groups ---the experimental and the control group. While assessing your results, you should compare the outcome for the patients that underwent the treatment with the condition of those who were not in the treatment (who were in the control group).
Finally, while assessing the results of your procedure (project), you should take into account yet another precaution valid for all similar projects: the double blind claim. The scholars who administrated the treatment should not be the same ones who are going to assess the results. The experimenters who administered the treatment should not be the ones who assess the outcome. The assessors should not know which patients were in the control/experimental group.
In spite of the fact that you may treat these precautionary notes as a nuisance, as claims of an all-too-high- an-order, you should nevertheless take them into account. And I hope that you have already done so while writing your proposal.
I wish you the best of luck, and the best possible outcome: for you as researchers, and all the more for the subjects of your experiment.
prof. dr. Darko Polšek
Head of the Anthropology Study Group
dpolsek@gmail.com
Disclaimer: The letter has been slightly edited for clarity; all hyperlinks to Wikipedia articles were added by the iGEM team.
