The PI Perspective: Operationalizing ADC and Multi-specific Antibody Trials

Transcript

Meet Dr. Squillante

My name is Christian Squillante. I am a medical oncologist at the MD Anderson Cancer Center at Cooper University Health Care. My primary responsibilities in my position are the management of solid tumor patients from a clinical standpoint, particularly thoracic oncology, head and neck oncology and genitourinary oncology. 

In addition to this, I serve as the co-director for the GU program at MD Anderson at Cooper and I also serve as the Director for Solid Oncology Tumor Research. So in that role, my primary responsibility is to help develop, recruit and open clinical trials for our cancer patients at our Cancer Center in the field of solid tumor oncology.

Understanding Antibody Drug Conjugates (ADCs) 

Right. So it’s kind of a new and developing field in the area of oncology. So if you think about classic cancer treatments and therapeutics, people tend to think about chemotherapy as like the stalwart of treatment for cancer and chemotherapy, the kind of the way I describe it is it’s like, you know, spraying weed killer on your entire garden, right? You’re going to get the bad stuff, but you’re also going to get some of the good stuff as well.

So chemotherapy is a systemic therapy. It goes generally into your veins and then gets to every cell in your body. So the good part of that is it can kill cancer cells. The bad part of that is it can kill good healthy cells as well. That’s where we get all our side effects of chemotherapy from. 

But antibody drug conjugates are really a newer type of cancer treatment that really kind of combines what we call an antibody or monoclonal antibody with a chemotherapy agent or the cytotoxic drug. And so I kind of consider these to be like the Trojan horse if you think about them.

The idea is that the antibody can get onto a cancer cell and then get inside of the cancer cell, and then once it’s inside the cancer cell, that linker kind of breaks apart and then that chemotherapy or that cytotoxic drug is now floating inside of the cancer cell and is able to do its damage and kill the cancer cell itself. So basically the Trojan horse sneaks in, opens up, releases the soldiers and the soldiers run around and are able to kill the cancer cells. So really ADCs are like the Trojan horse of new cancer cell treatment. 

So you know, this is a kind of a cool thing in that the idea is it can be much more specific to the cancer cells. You’re not spraying the whole garden, you’re just getting to the cancer cells themselves. And the and the hope is that, you know, you have a better targeted therapy that works a little bit more effectively with diminished side effects. 

Strategies to Mitigate Toxicity

Yeah. So again, this is an extremely complex area of discussion right now. So I’ll try to, you know, get some key points there in on this.

So when you’re talking about strategies for mitigating the toxicity of, you know, these antibody drug complexes or bispecific antibodies, you know, one thing for instance I think of especially with the bispecific antibodies where you can get these horrible reactions.

The cytokine release syndrome is what we call step up dosing. So it’s not necessarily coming in and just hitting the patient with the full dose on the first try. That would put you kind of most at risk for getting a nasty reaction. You know, it’s more so, you know, starting with a little dose, seeing how they’re doing, getting that immune system to adapt and like recognize the agent to minimize the risk of immune toxicity and then increasing the dose, often doing this in a hospitalized or closely watched setting.

Those are some of the strategies that are currently in place and being explored to kind of minimize that risk to patients from having a horrible side effect. 

Other strategies can include, you know, carefully analyzing and managing, you know, the pre-medications for a patient that are administered to minimize reaction.

And then you know, on the more cellular level, which is a bit outside kind of the scope of a clinical practitioner such as mine, but you know, we still understand this, it’s really 
developing and engineering the drugs for, you know, a more specific affinity for the antigens to minimize toxicity. You know, really getting those targets precise, really knowing what targets you’re using to minimize that cross-reactivity.

Those are some of the basic but main strategies I would think of that are being used to kind of help the toxicity of these drugs are off-label toxicities. 

Advantages and Challenges for Patients 
Right. So I think some of the big advantages are that we have proven in a number of cancers that bispecific drug conjugates and antibody drug conjugates can be very effective in the treatment of cancer. And they’ve really, you know, broadened our weapon arsenal against fighting cancer.

You know, classic chemotherapy, especially for patients with stage 4 disease, it works for a little bit. 
And then it stops working, and then patients can have limited treatment options. So we need more weapons to fight the cancer. So we have a number of these drugs that exist and they’re really broadening our ability to, you know, you know, overcome those generic chemotherapy mechanisms that become resistance mechanisms 
and give patients an additional option to fight their cancer.

So I’d say first and foremost, you have two new classes of medicines basically that are allowing patients to live longer and hopefully live better with their cancer. And that’s the second big advantage is that again for the most part you know, these drugs do have their own sets of side effects and you know, toxicities, but we can see significantly diminished side effects compared to classical chemotherapy with these treatments. And so I think those are two things that are a huge benefit to patients.

You’re talking increasing not just the quantity of their life, but the quality of their life. But like you said, that doesn’t come without some challenges that come with these drugs.

You know, one of the things is they’re generally very expensive. These drugs are expensive to develop, expensive to study and expensive to manufacture. So, you know, in the world of insurance in the United States, these can become prohibitively expensive and. 
Some cases. And so how do we manage the cost of healthcare and the development of these drugs? That’s a challenge. Other things is that they’re not perfect. You can still have, you know, off-target side effects, you can still have toxicity.

So how do we even better refine the targets of these drugs to minimize side effects. And then last but not least, we kind of touched on this a little bit earlier is that if I have a tumor, not every cancer cell in that tumor is going to be exactly the same. Some of those cancer cells may have the target, some of those cancer cells may not have the target. So the complications of what we call heterogeneity in the targets of cancer cells can make these drugs somewhat difficult to manage and you know, those are the things that we have to really work to overcome. 

Operational and Logistical Trial Challenges

You know, in the old days with clinical trials, although we had much less of them, you know, they were a little bit simpler. It was do you have the disease? OK, we have a drug that we’re going to explore in the disease. And so it was a pretty simple design.

But as we mentioned, you know, in a lot of these drugs you have to make sure that the biomarker exists. So the first thing is, you know, you have to be able to test for the biomarker, identify the biomarker in a reasonable period of time. You know, sometimes these can take weeks to identify and then make sure patients are positive for that biomarker. And so part of it’s defining the threshold, like what percent of the cancer cells need to have that biomarker? What percent of patients need to have that biomarker for you to consider them inclusions in the trial, you know that’s part of the things that go into the trial design.

And then you know pharmacokinetic monitoring when these drugs are in early phase development to kind of track like how available are these drugs to the cancer tissues that can be a little bit more challenging. 
That sometimes requires more specialized testing and monitoring that you know not every center is going to have.

And then lastly, especially with the bispecific antibodies as opposed to the single antibody drug conjugates, you can get some serious, serious immune mediated side effects, things like cytokine release syndrome (CRS) that can be even deadly in some patients. So some of these trials or even when we’re administering these drugs as part of our standard of care can really require very close monitoring of patients or even hospitalization. And that adds a whole other layer to the care of the patient and how you’re managing these drugs and how you’re managing these
trials and that can make the trial design more complicated.

I would say though, on a personal note, and I say this to my patients, more complicated doesn’t always mean we shouldn’t do it. It just means it’s something you need to be aware of as part of the quote- unquote cost of developing these drugs, administering them to patients. I mean, there’s a great value to these drugs in cancer care right now, even though it may be a little bit more difficult. 

The Value of CRO Support for Sites

Yeah. So when we’re opening trials that involve ADCs or bispecific antibodies, you know, you want to make sure first and foremost that the trial design is something that your typical Cancer Center can support. Am I able to get all your pharmacokinetic studies done within like the infusional hours window, like I we don’t want our staff there 24 hours trying to deal with some of these things cause that can definitely lead to burnout. So making sure that trial design isn’t so cumbersome for not just the staff but for the patient to be undergoing it I think is important. 

And then if there’s any specialized testing or equipment that’s needed, you know, you want to make sure that that’s provided, that the appropriate trainings are provided so that everyone’s on the same page and that the trial can be run effectively. You know, some of these things, like I said, are quite nuanced and people don’t have as much experience with them as compared to more classical agents, so you want to make sure the training’s there, that the support’s there, and if necessary, that the financial support’s there for the resources to be in place for, you know, the research nursing, the research support staff, the research techs to be, you know, engaged in the trial and be able to execute it effectively. 

The Therapeutic Landscape and Curative Potential

Well, you know, it is an exciting time. You know, I was just thinking about this earlier today that like, you know, in the 2010s we had this massive expansion of immunotherapy being developed for cancers, particularly solid tumors.

We had the development of CAR T cells for our leukemias and lymphomas. There was this huge boom in terms of identifying, you know, these immune therapy agents and we continue to have this exploration, just like you said, into multiple other classes of drugs. So I think this is a piece of the pie, right?

These are two classes of medications that work differently than immune therapy, work differently than chemotherapy, work differently than targeted therapy, work differently than radiotherapy, work differently than hormonal therapy.

So when you’re looking at the landscape and you have a lot of these different pieces of the puzzle of cancer care, I think, you know, currently we’re generally using these therapies alone as single agents in general. 

I think one of the big areas of exploration would be how do we start using these drugs with some of the existing agents that we have in combination or in sequence or as a form of switch maintenance.

You know, how will we use these drugs with our current arsenal to maybe work synergistically? Sometimes 1 + 1 doesn’t equal 2, sometimes 1 + 1 = 3. So if we can add these to some of our existing drugs, can we get more of an effect? I think that’s going to be an area where we see these drugs heavily developed and I think we’ll also see them being developed in different settings.

So you know a lot of these drugs are used in refractory or stage 4 medicine static patients right now will we start exploring these drugs in the curative setting to see can these not only work on cancer cells, genome increase, you know, cell death, but can we increase cure of cancer with these drugs?

I’d really like to see some answers come out with some of our existing and bispecific antibodies of can we move these into the more curative setting in different tumor cell types to see if we can get an increase in cure because that’s always our ultimate goal. We really want to increase cure.

So I suspect we will continue to explore these drugs in those contexts and I think finally and we’ve alluded to this already, you know exploring more specific biomarkers and more specific targets for these drugs to make them even more effective and less toxic.