Corey

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Revision as of 05:55, 29 May 2017

This is a discussion between Marc Perkel and Dr. Corey Zankowski of Varian who makes the Varian radiation therapy equipment used by Kaiser. Corry is the guy who designs the equipment.

https://www.varian.com/about-varian/leadership-and-governance/executives/corey-zankowski-phd

The way I see it - who better to design the radiation protocol than the guy who designed the machine?

My Initial Email

Hello Dr. Zankowski,

This is somewhat of an unusual request coming from a cancer patient, but I'm very high tech and hope to get your interest.

I am a patient at Kaiser and I have stage 4 NSCLC lung cancer. I talked my oncologist into trying something experimental as I am facing certain death otherwise. Have you heard of the "abscopal effect"? If not you can Google it but the idea is to use immune system stimulators with radiation to cause the immune system to recognize cancer as a target and go after it.

The abscopal effect has been noted a lot retrospectively where a patient is getting immunotherapy and then gets palliative radiation to stop a tumor from bleeding and a few month later the patient is cancer free. My goal is to try to trigger this effect. Kaiser is using your product and that's why I'm contacting you.

As I said, I'm high tech. I'm not a doctor but I learn really fast. My theory on what is likely to trigger the abscopal effect is not to try to kill the tumor but damage it in a very specific way. What I'm looking for is a pattern of radiation damage that puts necrotic dead cancer and dying cancer in contact with healthy tumor tissue so as to allow good interaction between the white blood cells and damaged and dead cancer tissue. I'm thinking that the damage should be towards the center of the tumor so that the collateral radiation damage will still be mostly within the tumor.

I have asked Kaiser for this and they say they understand what I want and can do it. I am contacting you however because I think the geometry of the radiation is very important and this technique has a good chance of working. I am wondering if you and your engineers want to get directly involved in planning a radiation geometry specifically to trigger the abscopal effect? If this works it will be very popular.

Marc Perkel Random Genius Gilroy CA.

Corey's Initial Response

Marc, I am sorry to learn about your diagnosis and I know how difficult it is to navigate the technical and medical fields to find the right option. Thank you for reaching out to me, and I hope that I can provide you some more understanding about the abscopal effect. Kaiser in Northern California has a very good radiation oncology organization, so you are in good hands.

We are very familiar with the abscopal effect, and you are correct that it is currently something about which we hear a lot recently. I am copying my colleague, Dr Deepak Khuntia who may be able to explain the effect in more detail. You seem to understand the concept very well. What we understand is that when a large enough dose of radiation is given to a tumor it is able to release a spectrum of dead, dying and damaged tumor cells along with their contents. These bits of cells lose much of the "cloaking" benefit they receive when they masquerade as normal cells, can are detected by the immune system. With the right type of immunotherapy agent, you can alter the immune system's self-regulation mechanism that normally prevents it from attacking tumor cells and it develops antibodies that circulate throughout the body attacking abnormal cells (hence the term "abscopal"). In some cases a second immunotherapy agent is used to cause the immune system to go into overdrive.

With respect to the geometry and targeting of the radiation, you are correct that it needs to be done carefully. For stage 4 NSCLC it isn't possible to irradiate every cancerous lesion because your body could not tolerate that much dose. I have heard of clinics treating the main tumor to a palliative dose (to reduce symptoms and discomfort that you feel), and to target small metastatic lesions with very high doses to stimulate the abscopal effect.

I will tell you about something that isn't generally known, but that Dee and I have started to hear about. You should discuss this thoughtfully with your doctor. The immune response is mediated by t-cells, which are very sensitive to radiation. The larger the volume of your body that is irradiated, and the longer the irradiation time, the higher the likelihood that the treatment actually impedes the immune response. You may be better served irradiating a few small lesions that are furthest away from high volumes of blood flow, with the highest dose rate available on the machine (flattening filter free, 6FFF or 10FFF, where 6 and 10 refer to the energy of the beam 6 and 10 mega-electron volts, respectively). The highest dose rate comes from the 10FFF, but the energy is selected often by the depth of the lesion below the skin surface. 10FFF is more penetrating.

Now, we employ some excellent dosimetrists who make the radiation treatment plans, and I'd be willing to have 1 or 2 of them look at your plans as long as you sign a consent form. But the treatment strategy needs to be decided by you and your doctor.

Please understand that today, the abscopal effect is not well understood, and there is no guaranteed method to achieve it. But we don't always need to know how it works to make it work.

Regards, Corey

My Reply

Hi Corey,

We are definitely on the same page with regard to everything you said.

the plan is to target the very center of the main tumor only with a high dose of radiation and create a pattern where there is a variety of dead, dying, wounded, and pissed off tumor but right next to good healthy tumor so as to create interaction between the immune system and the cancer. And - as you said - to not create a radiation burden that would suppress the immune system. I explained that my main tumor was going to be a "school" and not a "battlefield". I walked to the radiologist and their "chief physicist" and he sounded like he understood what I wanted.

However ....

I have had an unusual life and, quite frankly, I'm a lot smarter than most people. And it's not unusual for me to be far ahead of the experts. So I had already figured out most of what you are talking about, but you do have some new details that seem helpful. And I'm smart enough to email the people who designed the equipment figuring you had a deeper understanding - which you clearly do.

I have some license to do what I want because the first round of treatments I took were also a home brew cocktail of several drugs targeting RET fusion where I repurposed a thyroid cancer drug for lung cancer (Caprelsa) with Affinitor and 4 other substances. And it did rid me of RET fusion cancer. But I have non-ret-fusion cancer left.

Immunotherapy was always going to be my second line but I have no PD-L1. Then I ran across the abscopal effect which seemed perfect.

I understand that no one knows how to trigger it. So my job is to figure that out. But everything else about the abscopal effect is somewhat well understood.

My idea - try everything till it works. If I get it to work - I win.

I got an infusion on ipilimumab Thursday and starting radiation Tuesday. I'm thinking about getting nivolumab next thursday. Also going to try some hypothermia too and whatever else I can come up with. Then wait a month and try something different.

But ...

this is where I'm hoping to get you interested.

I think the key to triggering the abscopal effect is the geometry of the radiation. And I think you also have figured that out. I'm thinking something like disks of 2 dimensional damage near the center of the main tumor. I'm interested in the geometry you envision if you were going to trigger the abscopal effect in an 8cm tumor.

What would you design? And would you work with my team at Kaiser.

I think this has a reasonable chance of working, especially with the right talent involved.

Interested?

His Reply

Marc, I'd be interested in trying to help out. Dee is a practicing radiation oncologist with a great network, so we could bring a lot of talent to the table. You take the lead and we'll help as much as we can.

A 2-3 cm spot should generate enough damage to trigger the immune response without over-exposing too much healthy tissue, including the blood cells. I'd say the geometry is key to sparing healthy tissue. The total dose in a single fraction is more likely the key to triggering the abscopal effect. From what I've read from Zvi Fuks at Memorial Sloan Kettering in NYC, you want to deliver between 18-24 Gy in one shot. (A normal course of radiation is given in 30-40 shots of 2 Gy, so 18-24 Gy can freak out a lot of oncologists.)

Let me know how we can help, we're here for you.

Regards, Corey

My reply

What I'm thinking is that the right radiation pattern to optimize for abscopal is very different that that of any standard treatment. The idea is to create shock and damage to get the tumor to send danger signals. I want to make the tumor look like an organ transplant. I want it to feel like it was beat up by the mob.

I think you know what I'm talking about and you could develop a radiation protocol specially to create that effect.

This is doable.

His Reply

Marc, I think we can deliver almost any pattern that we need. We need to combine our heads to develop the right dose distribution that gets you some frighteningly high doses to some small active volumes. The penumbra, or normal dose gradient will create high to low doses that will create a spectrum of damage to the tissues, releasing a lot of antigens for the immune system to grab.

Let's do it!

Corey

My Replies

Also ....

All cancer are cells that somehow escape the immune system. So the immune system is the key to going all the way to a complete response. Also - I have no illusions, and I understand that what I have is considered short term 100% fatal, and the chances of a non-doctor like myself of figuring out how to cure it is a long shot at best.

But ... this is not that unusual for me as I'm used to doing things others consider impossible.

And ....

This abscopal effect almost seems too good to be true. It's like finding a football laying on the 1 yard line and walking it across the goal. All the had work is done. It's like it's just sitting there and all I have to do is trigger it.

How hard can that be?

For example - if you had a bad radiation machine, I could repair it. And I've never seen it. How? You have a service manual and start swapping out parts. And I could make good guesses about which ones to swap out.

The abscopal effect is the same thing. We understand that one of the steps is the bringing together of the immune system and dead cancer. That's all about geometry. so we (you) can create a pattern that optimizes just on creating that kind of contact.

Once that is done we try all the drugs and all the timing till we get lucky.

I have no idea if this will work for me. But I'm convinces that if we took 100 people and tried this that a lot of them walk out cancer free.

So ....

The solution is just sitting there. All we have to do is pick it up and claim it. To me - this almost looks too easy.

What am I missing?

What I'm thinking is that the right radiation pattern to optimize for abscopal is very different that that of any standard treatment. The idea is to create shock and damage to get the tumor to send danger signals. I want to make the tumor look like an organ transplant. I want it to feel like it was beat up by the mob.

I think you know what I'm talking about and you could develop a radiation protocol specially to create that effect.

This is doable.

Obviously you are both a doctor and an engineer. I'm more in the engineering world. I see this as an engineering problem. I think the geometry can be calculated and we (you) can publish pattern files for anyone trying the abscopal effect.

In my case I'm looking to try and get lucky and they can figure out why it worked later. And this can work on a very wide variety of cancers. I see this as something that moves the needle.

First I want to say that I can not thank you enough not only for answering my emails, but understanding what I'm talking about. That's rather amazing. I feel like you totally get the abscopal effect like no one else I've talked to.

But there's a scheduling issue.

Last Thursday I got an infusion of ipilimumab and I'm scheduled to get my first radiation treatment on Tuesday. I don't know what kind of treatment they came up with because it's not traditional that they share that with the patient. But - I do have CT scan images and feel free to share these with anyone. These images are about 2 months old.

http://www.perkel.com/ct.zip

So I'm hoping they have something that's good enough for a first try. But I want to make your protocol my second attempt. I'm concerned that I don't want to waste a try because of delays.

Do you agree?

Also - I won't be able to contact anyone until Tuesday morning and they probably have work backed up. So I'm thinking I go with the flow on Tuesday.

I also want to say that I'm willing to sign anything that you need signed. These are my choices and I take full responsibility for these decisions. This is all a guess and I'm guessing that you are in a position to make the best guess - even if you turn out to be wrong. And I'll keep confidential any sensitive information that you don't want disclosed.

I am 100% sure that my team at Kaiser would be very interested and thrilled to work with your team. My oncologist is a very sharp doctor and he has always been willing to go along with anything that makes sense. My radiologist is very interested in this as well and she goes out of her way to educate herself and to bring in her "head physicist" to meet me. So I think they would be very cooperative.

And then there's me and I learn very fast. I think so far outside the box that I don't even know what the box is or how anyone git in it in the first place. My background is electronic repair and design, computer hardware and software design. I'm self taught and self employed in the junk email filtering business. Sort of an electronic version of the immune system. I tend to think big and they idea that I'm not a doctor and trying to cure cancer is not something I see as an issue for me. And I'm hoping that you also see this as a solvable problem.

I personally not only think beating cancer is doable - but the solution is just sitting there waiting for someone to do the last step - just trigger it. And that looks to me like one of the easier steps. I think that this should be solvable with the right minds and I feel like you really get it as to the geometry part.

I'm available as well over the next 2 weeks. Let me know when your free and I'll be there.

His Replies

Marc, I am a medical physicist by training, not an oncologist. Dee is the oncologist, and I think he should be a part of this conversation because we work closely as a team-- and I cannot prescribe radiation.

I certainly don't mind you sharing this conversation with your oncologist and the radiation team. They should working closely with your immune-oncologist in order to get the sequencing of the treatments just right.

To answer your question about coming to Palo Alto, we can arrange something, but we'll need to see your treatment plan and the CT images from your oncologist. We could share a screen and review your treatment plan together that way.

I am in town for the next two weeks, with some half day meetings throughout, but should be able to juggle a few things to make some time. Let Dee and me know when you've talked this over with your care team, have them send us the treatment plan and images to look at, and we'll all review together. On the Varian side, we'll also have to enlist one of our dosimetrists who is expert at designing treatment plans. All together we'll come up with a great strategy for you.

All the best, Corey

Try this. This video has overly simplified the graphics, but it explains things very well. I would think that you are talking about a radiosurgery treatment, which is highlighted. Small target volume, very high doses, very few fractions. (Hit it hard once, or a few times only)

https://www.youtube.com/watch?v=7ckb41KHv-A

This video from Stony Brook talks about radiosurgery, and Dr Ryu also mentions how it can be combined with Immunotherapy

https://www.youtube.com/watch?v=2QPEwhfJwyk

This one from CTCA talks about the process. Although they aren't using Varian equipment in it, I think it reinforces the statement that radiosurgery and immunotherapy together hold incredible promise for lung cancer treatment.

https://www.youtube.com/watch?v=fqRkz1uXH1k

I did not watch the entire video, but you might learn a lot from this presentation.

https://www.youtube.com/watch?v=67l1z_w8fkM

Ideas I sent him

At this point I'm lacking a good immunologist who really understands the abscopal effect. The one I talked to at Kaiser just didn't seem to know very much or wasn't prepared to have a technical discussion with a patient. If you know a really smart immunologist, that would be great. I have been watching a lot of YouTube videos to educate myself. But this is not easy stuff to understand.

Do you know a good immunologist?

This video by Dr. Polly Matzinger seems to be very educational to me. https://www.youtube.com/watch?v=9fktuiLkTrw&t=1622s

The way I see it the goal is to turn my primary tumor into a school - not a battlefield.

There are questions that need to be resolved.

When creating a school for the immune system, do the white blood cells want to see dead cancer, dying cancer, or both? And how much of it? Is more better than less?

Do we do fractions or a single strong hit - and why choose one over the other?

I am also aware that collateral radiation needs to me minimized. I was already aware you your concern that radiation reduces the immune response by killing t-cells. And damage to normal tissue can cause an autoimmune response to normal tissue (an abscopal effect against the wrong target). So it make sense to me to focus the damage central to the tumor so that collateral damage is still mostly within the tumor.

I'm also of the opinion that there needs to be good contact between dead tumor and blood supply so that the immune system can get in physical contact with dead cancer cells to learn from. In my mind I'm picturing a disk or partial disk burn area (ablative) so the surface of the disk is dead tissue next to undamaged tissue. More of 2 dimensional structures or multiple disks. Or is something that has properties like a fence lattice better? Should the damage be flat or textured?

How thick does the damage need to be? If thin is as good as thick then less radiation is needed.

I think that the best damage with the least radiation is our goal.

Anyhow - just sharing some thoughts.

From what I understand regarding the immune response is that the t-cell expansion happens after the antigen is recognized as an enemy, so the immune attack starts after the radiation has stopped.

I need to understand in more detail what you are referring to regarding t-cells and radiation. Do you have a link to something that explains that? I'm not seeing where I can screw things up.

As to my plan for Tuesday - I don't think they can be ready that quickly to meet with you. So the choice is to go ahead for one day or slam on the brakes. I'm going to need a good reason to slam on the brakes.

Also - trying to understand fractions. Why would I (or anyone) was fractionated radiation? I'm thinking an easy modification I might ask for would be twice the dose - half the doses?

I haven't seen their plan. I am going to ask for details first. And I'm going to have to make a decision based on what they came up with. It is possible they have a good plan. I did describe in some detail what I wanted.

Ultimately I figured there would be several attempts and I always thought me second attempt would be better than my first one.

But if you have something to tell me - I'm listening.

Also ...

I really appreciate the speed that you want to get involved and I like that. But this is a 3 day weekend and my Kaiser team isn't going to even be aware of this till they read their email on Tuesday, and who knows what time they will get around to reading their email.

And ....

I'm the patient and they are culturally not accustomed to having the patient play a lead role in designing the treatment. And they are not used to having the patient, who is not a doctor, have a deeper understanding of the problem than they do. So it takes a little longer and there are steps involved to ease them into it. I'm going to need to fill out paperwork to allow you to have shared access to my medical information.

So it could take a few days to do introductions and get things going. And it could take a few weeks to come up with a really good plan.

But I'm thinking early July for my second attempt. That's when we'll do the plan you design.

Will that work?

He Responds

Marc,

Thanks for letting me know. That’s perfect.

I have one issue that I think you should bring up to your oncologist before you receive treatment. If you want to stimulate the immune system, you will not want to receive a lengthy treatment to a large volume of tissue Tuesday. From what I understand from 2 recently described models, you’ll want to minimize the volume of blood that gets irradiated. Since I’m not sure what Tuesday’s treatment looks like, and I’m not sure about how long it takes for the T-cells to be replenished with new ones, Tuesday’s treatment could compromise the abscopal effect you want to achieve.

I’ll talk to Dr Khuntia tonight (my mother is going through a recurrence right now), and will ask him if he can take a call with you either tomorrow, or Tuesday with your care team. (I don’t want to throw a wrench into your current treatment plan.)

Regards,

Corey

More of my ideas

Thanks, I just watched all the videos. The first and the last one was most interesting.

I'll start with questions about your machine. There was a point where they used the word "beams" instead of "beam". Do you have beams, and what does that add?

From what I see the culmonator can create any shape beam. I assume that the beam is still a column - beam comes out the other side of the patient the same size and shape it went in?

The last video was very informative. I had seem a lot of things like this in other videos but this was a very good presentation.

I see where he is talking about radiation killing T-Cells - but I think you are over reacting to that, and here's why.

In all of these videos that talk about irradiating the tumor and how may grays, but they never talk about doing a fraction of the tumor or the geometry of the damage. It is as if they are hitting the whole thing with a wide beam, and that won't work.

But ....

If we are doing an intense 2 dimensional attack just to the center of the tumor we aren't going to hit many T-cells. And we aren't going to damage very much skin tissue or lung tissue because the total radiation is very low. It's just concentrated in specific areas.

Also be irradiating the whole tumor you kill off areas what bring blood to the dying cancer so the lymphocytes never get in contact with cancer DNA to take back to the thymus.

This is what I believe the geometry is important. In the abscopal example in the last video, the patient received palliative radiation to relieve tumor pressure. That was surgical and it left dead tumor in contact with live tumor and that's the trick that made it work. There is no standard radiation treatment, yet, that I think is optimized to abscopal. And I personally believe this is at least one of possibly many steps to get this right.

The correct radiation geometry will create the right amount of dead cancer and do so in a way that you have maximum opportunity for the lymphocytes to interact, and is calibrated so as to do as little damage to non-tumor cells as possible. That's why I'm picturing something like a dime inside an egg, Or several dimes inside an egg. But you would be better than me at this.

So - our new idea we are adding is the geometry. I think it's a key to making this work.

And - of course - I need to get the immune system right. Various immunotherapy drugs. I'm thinking maybe get vaccinated for something during the process. Vaccine adjuvants. Hyperthermia to create heat shock proteins. Eat my green vegetables.

Here's a wild geometry idea. Just thinking out loud.

Imagine the center of the tumor sliced up like the segments of a tangerine. Let's say 12 equal segments. Think of a dime rotated on the vertical axis every 30 degrees.

So at first you have necrotic cancer on the surfaces of these segments that interact with live tumor. But as time goes on - because the center contains such thin wedges of live tumor - over time the dead area grows creating a constant supply of dead tumor over a longer period of time. Maybe we can also even create damage in the outer wedges that might spread over time? Maybe come back later and cut each wedge in half?

More death. less radiation.

I'm thinking ....

More tumor surface + secondary necrosis + over more time = good plan

Anyhow - popped into my head. Hope it's useful.

Another thought ....

Texturized damage?

Instead of using a square beam we use a + shaped beam like the Red Cross logo? That would increase the surface area of the damage and the corners would get rounded off over time by necrosis.

Hope I'm not sending you too many emails. At least some are short.

Thinking about your pulsed beam mode. Am I thinking right that if you wanted separate columns of radiation rather than an arc of continuous radiation that you would do an arc and pulse it?

Also ....

Imagine this. We start with the tangerine slices like I described in the last email. Then a month later we come back and rotate the axis 90 degrees and do another tangerine? Then a month later we rotate to the third axis and do a third tangerine.

That would create a growing necrotic area where the tumor would slowly rot from the inside out and create a continuous supply of fresh rotting tumor. And with a minimum amount of radiation.

What do you think of the idea of getting the tumor to rot?