Are there general strategies for adapting drugs to click-chemistry or is there something special about doxil that makes it amenable to this approach?
To me it seems like one upside of using a well known chemo agent is that the oncology community is going to be familiar with it and possibly more receptive to adopting it into their practice. Probably will help with the approval process too.
Is the delivery method a major aspect of the trial? Could the biopolymer be adjusted to also provide embolization and/or doped on some of the materials used for Y90/SIRSphere type targeted radiotherapy?
This really seems like a cool idea, I wish you and your team the best!
That is absolutely right. By honing the drug to the tumor, and minimizing the effects on the rest of the body, you are essentially able to unlock power on the tumor that would have put the patient's life at risk before.
Taken it even a step further, if you have a system that selectively gets the drug to the tumor, then you can give combinations of cancer drugs that would be otherwise lethal, also preventing the possibility of mutations that would make the tumor unaffected by a single drug. The possibilities are immense.
The CAPAC technology allows you to give multiple daily doses of the therapy for 5 consecutive days after injecting the tumor with the biopolymer once. This is a significant advantage to needing to inject the tumor daily.
thanks for the response. this is awesome work you're conducting. if you can inject directly into the tumor, why not do a high enough dosage to kill the tumor in one shot?
Because this cannot be achieved with one dose. Also think about diffusion in tissue of small molecules. Essentially within an hour or two, anything that you injected in the tumor is gone. So now you are asking about killing everything with a drug in a specific part of the body within one hour without much damage to the rest of the body...
It does not sound that easy anymore and that is probably why people resort to surgery, in other words remove the diseased tissue. The problem is that it is often hard to make sure you have removed all of the diseased tissue and you have “clean margins” and none of those cells have already infiltrated areas of the body where you could not detect them. In other words, a pretty challenging problem. Having another tool available to fight this disease would be significantly beneficial.
Thank you for your comment. Congratulations on your positive response and recovery.
Our goal is to enable the same response in others who may experience side effects and may have to forgo treatment because of it.
Doxorubicin, also nicknamed red devil or red death, is notorious for its side effects. In addition to the bone marrow toxicity common to most chemotherapies, a person cannot receive more than 6 doses of doxorubicin in their lifetime without increasing their risk of heart failure. So when patients respond to doxorubicin, but more doses are needed, the patient and the doctors face a difficult choice: risk of death from the cancer or risk of cardiac failure. Shasqi is trying to change that equation for solid tumors. We are not focused on lymphomas yet.
1. Cancer is characterized as local tumor, locoregional or distant (metastasis).
2. Our approach can certainly help patients with local or locoregional disease.
3. As we have presented in multiple cancer conferences, our approach seems to also help with distant disease, because by focusing more powerful therapy to the tumor, sparing the rest of your body, we give the body the opportunity to recognize the tumor as foreign and fight it.
https://cancerres.aacrjournals.org/content/80/16_Supplement/...https://www.biorxiv.org/content/10.1101/2020.10.13.337899v1
There has been a recent wave of intratumoral approaches particularly for immunooncology (e.g. TLR, Sting, oncolytic viruses) and there are manuscripts in the scientific literature about the technical challenges and possibilities (https://jamanetwork.com/journals/jamanetworkopen/fullarticle...).
So, to your question, yes it is specialized, but not particularly difficult. We have taken great care to leverage the learnings of those experts to minimize the challenges of interpatient variability.
But we will only know for sure if our efforts where sufficient once the human clinical data comes back. For now I can say that our preclinical studies are highly encouraging.
Historically, and probably the mainstream hypothesis, is that you need chemo to be systemic in order to take care of micrometastatic disease (tumors that you cannot see). However, with the advent of immunooncology (IO) therapies (drugs that help your body recognize the tumor) and the benefits of having chemo + IO drugs is challenging that dogma. Certain chemo drugs are known to trigger an immune response. Having a technology that gives intense amount of chemo at the tumor and without diminishing the persons immune system. Our technology opens the door to have this effect in humans. We have seen those effects in mice studies and presented the results in cancer conferences.
Thanks so much for answering! I think what I'm trying to understand is why you'd want to target chemicals if other options like surgery also are targeted. Is the application then for tumors that are hard to remove surgically?
Surgery is not a great option. It’s incredibly invasive, it’s risky, it costs valuable time to schedule, it’s expensive and at the point where you’re metastatic it’s not curative in any way.
I haven’t read the article, but if you can integrate this with regular chemo cadence to amplify effects at certain locations it seems like a no brainer.
Exactly. For us at Shasqi, it was about combining the spatial control of surgery with the temporal control (flexibility of dosing) of oral or intravenous drugs.
This is Jose, CEO of Shasqi. There are three firsts that Shasqi announced this morning:
1. First time click chemistry is used in humans.
2. First YC company to reach first-in-human clinical trials
3. First two patients dosed for SQ3370 in Shasqi's Phase 1 clinical trial
My girlfriend had breast cancer twice already, and actually I was quite scared that she told me that she would almost rather die thank go through chemotherapy again, it was so bad for her (she's been through more than 15 operations, but she doesn't care about that). Currently it looks that she can't ever stop taking anti-estrogen drugs ever in her life even though it has lots of side effects.
My question is: most of the drugs fail at one of the trials with much more than 90% probability. What is the chance you give your drug to be succeeding, and how did you get failure rate probability under that 90%? Also what's plan B?
Sorry to hear about your girlfriend. I have heard those feelings as well. They are not uncommon.
The probability of success changes as you move further in the development. Below there is a link for a booklet that talks about the general pharma odds in page 53.
In our particular case, we took a known chemotherapeutic agent called doxorubicin. It has been used for the last 40 years in about a dozen types of tumors (include certain types of breast cancer).
The problem is that 3 out of every 4 patients end up major side effects to their immune system (e.g. neutropenia), but even worse, you can only take about 6 doses in your whole life, otherwise your risk for cardiac damage increases very rapidly. It is known colloquially as red death and red devil, because of its red color.
Using that drug as the starting block for our approach improves our probability of success and helps us know what to expect in terms of side effects.
The problem with my girlfriend is that she thought she went through it, but after 4 years she stopped anti-estrogen therapy because she wanted a baby, and 1 year later her breast cancer got metastatic.
After new extremely complicated surgeries where most surgeons said that it's impossible to get the tumor out of her body (there was only 1 surgeon who took the chance), now she's back on anti-estrogene therapy and it seems that she can't ever stop it again in her life, or at least until some better therapy is available.
I'm quite hopeful of the liquid cancer biopsies though, detecting the small amount of early stage cancer DNA inside the blood will get useful as the thoughput of DNA sequencing increases exponentally, but the cancer curing trials look promising as well.
To have a minimally invasive sensitive and specific test would be a great addition to the toolbox against cancer. However, if it comes back positive, then what comes next? Maybe surgery? But if we had therapies that were highly effective and could concentrate the cancer drug at the tumor with minimal side effects that may be preferential or supportive to going through the operating room, anesthesia and necessary morbidity of surgery. And potentially you could do this multiple times if needed.
To take my girlfriend as an example, she found her tumor in time when it could have been managed probably without chemotherapy, but as she was only 30 years old, the doctor said that it's probably not tumor and that she should go back 1 year later. Now of course BRCA mutation testing is much more known and available, but this was 10 years ago.
The reason why I'm more hopeful about liquid biopsies than greatly improved cures at this point is because it depends on an informational technology that is relatively predictable, and has a high chance of success for many types of cancer at the same time. Testing has 0 side effects, and can be done for $2000/year in a few years, as the providers are not planning to go through insurance companies first. Also it can be launched globally as long as the blood withdraval can be taken care of.
Shasqi's goal sounds amazing, but it needs to go through all the clinical trials, it has to be covered by health insurance, which takes much more administration work, it has a 10% chance of success for the first time (as it's in stage 1 trial right now), and will take at least about 5-10 years to succeed for just 1 type of cancer, even if it's an extremely important type.
Congratulations, reaching that stage is very impressive and could be life-changing to a lot of people.
> CEO Dr. José M. Mejía Oneto, who has a PhD in organic chemistry and trained as a medical doctor
As an electronics PhD student with a growing interest in medical applications of my skills, how does one go about training as a medical doctor? Are there shortcuts one can take if not intending to practice? Though at this point, it seems to me that recognition/credentials is a bit orthogonal to building up knowledge.
If you are interested in medical devices, at least in the US there are hospital-based postdoc positions which will hire some engineering PhDs even w/out specifically medical thesis focus (as you are coming from ferroelectrics: potentially MRI or robotics research). In such a position there is a lot of opportunity to attend medical lectures, and also ideally to shadow MDs in clinic, observe procedures, and sit in on case reviews.
There are also various 1-2 year MS degree programs, often called "MS in biomedical sciences", which can function as a bridge into medical careers. Some are designed to prepare for MD or other professional school, while others have a focus on broader background (variety of subjects like anatomy, physiology, and pharmacology).
That is an interesting question. Thank you for sharing. Indeed, I was a chemistry PhD before going to medical school. Unfortunately, there are no easy shortcuts that I know of. Interestingly it is a bit unpredictable if somebody will practice medicine or not when they go to do an MD or MD/PhD.
Thank you for your answer. After nine-ish years of higher education, I'm not sure I want to double down on that. Not right away, at least.
Another option is to learn on the side, and ask actual doctors to confirm/infirm theories and assess feasibility, but without credentials, it's easy to get dismissed...
As far as I understand, that means they went to medical school.
A quick google search shows that Dr. José M. Mejía Oneto went to the University of Minnesota and did their residency at UC Davis. All this was done after their PhD in Chemistry from Emory.
I don't know if there's any other way to get medical training that will give you any level of authority or respect other than medical school (or related profession like PA or Nurse)
Maybe Dr Oneto can clarify but it does not appear he completed his surgery residency. This is not super material with respect to what he is doing now, but I believe this is why such unusual phrasing is used in the article. It is likely Dr Oneto still passed his medicine boards and is a licensed MD, he just is limited to taking care of post surgical patients (moonlighting) and is not able to perform surgeries in California.
Great work. My money is still on the wall on whether localized chemotherapy will be as/more effectivr, but you've been as systematic as can be and it's worth a shot to test in humans. Glad you used syngenic models instead of xenografts.
Ive been out of touch in this, could you clarify what is the current scientific consensus on the role of immune responses in chemotherapy efficacy vs. direct killing? How does your approach fit into that model?
Further,Could you comment on the immunogenicity of the tumor model you used to test the drug? It's a cell line from the same strain but it's still a line with probably a ton of mutations. Have to tried to establish tumors with more benign cells (or spontaneous tumor models ) to see if the efficacy can be matched in such scenarios as well?
Thank you for your comments.
With regards to your questions.
On chemo leading to cytotoxic vs immune killing
I am not sure that we have reached the point of a consensus on this. I would say that there is more and more evidence of the involvement of the immune system even with therapies that were considered exclusively chemotherapies. I would suggest looking up the work of Guido Kroemer on immunogenic cell death.
On the CAPAC approach fitting that model
Well, our inclination is that our current knowledge is limited by what can be achieved with our current dosing technologies.
For instance, in the specific case of Doxorubicin, you cannot give more than 75 mg/m2 without significantly endangering a person’s health. Assume that only 1-2% of that dose actually reaches the tumor.
How would you know what 10x that dose at the tumor would do? Also how could you separate the effect on the tumor and the side effects that it causes?
About 20-30 years ago, investigators were experimenting with increasing the dose by 20-30% by providing highly risky interventions such as bone marrow transplant. Not surprisingly those studies showed that the toxicity from the drugs was leading to deaths more quickly than the actual disease, so the efforts were abandoned.
We believe that the CAPAC technology allows one to explore biological effects, including a potential activation of the immune system that we have not been able to explore yet. And that is only talking about a single chemotherapy. Imagine if you could have at your disposal many cancer drugs with different mechanisms of action all working at the tumor site at the same time. The effects could be revolutionary.
With regards to the tumor model
We have used different syngeneic lines (fast growing, slow growing) and they all point in the same direction.
We have not tried yet spontaneous tumor models.
By the way, the efficacy is not matched with that of conventional doxorubicin. The efficacy is surpassed with fewer side effects.
Thanks for the answers. Your model does sound promising, and I see you have gathered as much meaningful information as possible before human trials. Good luck and hope it exceeds expectations!
Hello Jose, I wish you success in such an important endeavor.
I have a question, but it is more of an advice one, rather than specifics about your company. I am going to soon embark in a Masters program for medical research, then medical school after. What advice do you have for a novice that is interested in the idea of starting a biotech company in the future? What are the things I can do now that can set me up for the future with regards to starting a biotech company?
I am not sure that there is any one path or unique suggestion. But my general advice was to stay curious, learn as much as possible and keep an eye for what could be, rather than just accepting things as they are.
Also I strongly believe in the cross pollination of concepts leading to unique ideas. So having some sort of orthogonal knowledge in addition to medicine is helpful (e.g. business, chemistry, biology, programming, etc).
Yes. Any solid tumor that is accesible for an injection and we have reason to suspect it would be sensitive to doxorubicin, would fit the criteria of this phase 1 study.
For more info on the clinical trial please visit:
https://clinicaltrials.gov/ct2/show/NCT04106492
Thank you. We are very proud of what the team has accomplished and optimistic based on what the CAPAC platform has shown in preclinical studies. The unique aspect of this is that it is based on chemistry not biology so it seems that the reproducibility across species (and hopefully across patients) is better.
We have an investigational product, which means it can only be used in the context of a clinical trial.
All products that eventually reach the clinic have to go through this step and rigorous testing before being available to physicians and patients.