nterventional program specialist, chief of medicine and director of Gastroenterology and Endoscopy, City of Hope, Phoenix, and the founder and chair of the 

Endoscopic Oncology special interest group

Experts discuss next steps for research, including vaccination strategies, personalized cellular therapies, and more.

Leveraging Immunotherapy in GI Malignancies: Looking to the Future

OncChats: Leveraging Immunotherapy in GI Malignancies

, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, discuss next steps for research, including vaccination strategies, personalized cellular therapies, and more.

All of this is certainly exciting. All of us want to move the needle forward. To kind of wrap this conversation, if you had a crystal ball and you were to look into the future, [when it comes to] trying to intervene earlier on, trying to change the stage shifting, and hoping to improve survival, what do you see is the biggest challenge from a drug or therapy development standpoint? Dr Sharma?

Heterogeneity is a big challenge. Basically, a lot of the genomic therapies are predicated on specific alterations, [and we] will develop drugs for them. If you look at the evolution of the genomics in any solid tumor, specifically gastrointestinal malignancies, what happens is there are some truncal mutations, and then they branch off into many different kinds of mutation profiling, for instance. So, the question is, [for] which of these can you really intervene? We can talk another time about whether approaching drugs at these truncal mutations that are common to all the tumors is a good, personalized medicine approach; those have been generally not targetable in the past, but we’ve made significant advances in targeting them. That’s one side of things.

The other part of it is—and I’m super excited [about this], we’ve done some work and other people are working on this—the development of very potent vaccination strategies. Tumor vaccines have not been very successful in the past, but that’s been because specific hypotheses haven’t quite panned out. When I was a fellow, a long time ago, people were trying to develop a CEA vaccine, but that usually meant that you had chosen CEA as the enemy to kill, so to speak. For a variety of reasons, that didn’t work, but one of the main reasons is heterogeneity. Number one, what is the real role of CEA on the surface in tumor biology? That’s unknown. Number two, heterogeneity; a lot of cells may not have that. So now, we have much more sophisticated approaches in figuring out what kind of vaccines to develop, and how we can do what I call personalized vaccines or personalized cellular therapies. Those [approaches] are going into the clinic imminently, in the next few months. We can maybe talk about those another time, but [that’s something that] we could bring to bear in addition to the immune therapies, for instance, which we discussed are having a nice effect.

These are all technologies that have come out of genomic characterizations, and early understanding of tumor evolution, which is another thing that we have made significant advances with. So, certainly, those are the things that are going to lead to more advances in this field. Once we have personalized vaccines, then that would be the area where we could really change the trajectory, hopefully, from the Kaplan-Meier curve all going down directly into the toilet, to having possibly a tail on the curve, so to speak, where, we would have patients who would potentially get interventions that we still do, like chemotherapies, early interventions, but then stabilized, or get a much more robust kill rate using either these kinds of immune strategies or personalized medicines that actually attack more common mutations that have been previously considered undruggable.

Thank you. I’m an oncologist. You have to be optimistic.

Thank you for sharing your expertise with us today; this was fantastic. We value your time and your knowledge.

Thank you so much, Toufic and Madappa, for inviting me. I appreciate it.

Videos

In this episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts discuss next steps for research, including vaccination strategies, personalized cellular therapies, and more.

Experts discuss research efforts being made with organoids to address existing questions with immunotherapy.

Leveraging Immunotherapy in GI Malignancies: Research, Including Organoids and Ablation

, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, discuss research efforts being made with organoids to address existing questions with immunotherapy and the exploration of multimodality approaches to improve outcomes.

[We also know] that different tumors and different metastases are responding differently [to immunotherapy]. How much of that is the tumor itself? How much is the tumor microenvironment? I know you have also done a lot of work with organoids. What have you learned about the tumor microenvironment, and can we manipulate that to help with immunotherapy? Almost certainly, this discrepancy we’re seeing between [liver] metastases and lung metastases, as an example, is probably not due to tumor-intrinsic effect; it’s due to the microenvironment effect. The liver, as we all know, is a highly immunosuppressive environment because [it] is a detoxing organ; it has evolved into an immunosuppressive entity so one could argue that’s why immune therapy is not working very well.

However, we started an organoid program 4 or 5 years ago, and now we have a huge, array of [research]. We take biopsies of these patients, and we sort of grow them in high quantities in 96-well plates, etc. Then, we’ve developed these immune organoids, where we can layer the immune cells on top using inserts on these plates, and we combine this with the genomics of the particular person and try to develop new hypotheses. Our paper is going to [be published] soon, and it shows how this can add to the options that the patients might have because right now, the best genomics that we all use is primarily a DNA-based genomic alteration. Those [alterations] are present in maybe 15% or 20% of patients; the rest of them are either not targetable or not present.

We’re trying to expand that horizon using RNA proteomics, and then we can test those hypotheses that come out of these kinds of ohmic analyses on the organoids and hopefully try to cull down the number of things we can use on patients and hopefully they’ll be more effective. We can also use these models to develop hypotheses about early polyps and what we can do to manipulate early cancers. We’re working with other gastroenterologists to create organoid models for early cancers or more high-risk polypoid conditions to see if we want to detect chemoprevention strategies. In patients who have a large number of polyps, do we want to do an intervention? These models can also be used to study that.

In looking at multimodality therapy, the comment you made about [loving to] working with gastroenterologists, it's the other way around, we love working with oncologists; we learn so much from them. The endoscopists have the ability to get tissue safely and to potentially impact the tumor through ablation, for example. Do you see any future role for ablation combined with immunotherapy to manipulate the tumor microenvironment? There are many modalities currently available for cancer ablation that we have endoscopically.

Yeah. I think we’re just opening the curtains here, and there’s going to be lots of different things that we can combine with immune therapy. Obviously, I know that you have a lot of interest in ablation, and we have a lot of patients, like Dr Kundranda was saying, young people who have lots of esophageal cancer, for instance, or cholangiocarcinoma, even colorectal cancer, that is metastasized where we can use ablative techniques along with immunotherapy and that’s going to hopefully increase local control but also systemic control. All those trials are coming. That’s the exciting future that we have. As things get better, early detection comes in and I think we will make a very big change here in the next 4 or 5 years. I’m really optimistic for the first time in my career with GI oncology.

I think you’re spot on, Dr Sharma. Previously, we would always look at our gastroenterology colleagues not as a truly integral part of our team but as the ones who would help us. But right now, when I think about our GI oncology team, it truly is a medical oncologist, radiation oncologist, surgical oncologist, and [others]. It has been truly remarkable [with regard to] some of the stuff that we can do, even with, like you mentioned, the combination of ablation with IO therapy or any of these modalities, which can certainly help kind of improve the immune response.

In this episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts discuss research efforts being made with organoids to address existing questions with immunotherapy and the exploration of multimodality approaches to improve outcomes.

Experts discuss the potential benefits of utilizing immunotherapy approaches earlier on in the disease course.

Leveraging Immunotherapy in GI Malignancies: A Shift in Drug Discovery

, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, discuss the potential benefits of utilizing immunotherapy approaches earlier on in the disease course.

Currently, most of the way we cure or treat early cancer is procedure based or surgically. Do you see drug discovery potentially shifting focus to using drugs to treat early malignancy? Or some kind of transition to immuno-oncology in that area?

As you all are aware, [there has been] recent success in treating rectal cancer in a microsatellite unstable type area [in that] radiation combined with immunotherapy gave a very high response rate. That’s an area where surgery can be difficult for patients and [can impact] quality of life. I think that’s a very good example. Obviously, that example [has to do with a] small number of patients. I do think there’s a huge potential as therapies become more effective. One of the things that one has to realize in oncology is that marginally effective therapies in metastatic disease can actually be very highly effective if used earlier. There are examples of that in oncology and [specifically] in breast cancer, for instance, where [if a patient has] HER2-positive breast cancer and metastatic disease, then [these agents] are quite effective but they are not curing the patient. [However,] if you use [those therapies] earlier on, they actually cure a lot of patients. We’re talking about marginally effective therapies in metastatic disease [that are] curing people when used earlier. [So to reiterate,] this is another thing to think about in GI oncology, where a lot of the therapies medical oncologists use in the advanced setting are not necessarily that effective, but as they become more effective and they’re used more in the earlier setting, more patients will be cured.

We are making some advances in the more garden-variety colon cancers with immunotherapy. I mean, the latest data on some other checkpoint inhibitor combinations look quite interesting and are showing efficacy in the metastatic setting. Again, the tail end of the curve is still to be determined but [I think if] those [approaches] were used up front, we’re likely to see much more efficacy in that setting than what we’re seeing in the metastatic setting. But certainly, that paradigm of moving therapies up front is moving forward more quickly than it ever used to be. I’m old enough to [have been around before] these [kinds of] trials were being done. But now, we’re moving [these agents] up front more quickly because we want to have more effectiveness [with] these therapies.

I think you hit on two key points with regard to this, Dr Sharma. [One] truly [has to do] with younger patients being diagnosed. We’re seeing a lot of these 20- and 30-year-olds in our colorectal and esophageal clinics [who have] metastatic disease or locally advanced disease. One of the key things is organ preservation. Although it is 5% to 8% of these MSI-H patients with rectal cancer achieving a complete clinical and radiological CR with organ preservation certainly seems to improve their quality of life as opposed to somebody having an ostomy. So, that has certainly made a huge difference for a lot of patients.

The one thing that is actually exciting that you did touch on is that when we look at immunotherapy, in this microsatellite stable patient population, which is the majority of our patients, our successes have been minuscule. We are making better progress [though] looking at the whole spectrum of immune-oncology. Within immuno-oncology, the one challenge that we’ve seen is that the clinical field has moved faster than the basic science per se. We’re seeing responses, and then we’re looking and questioning, “What is it that made that patient respond?” Then, we’re identifying those patients.

Do you see this changing in the context of whether you’re using IO therapy in the neoadjuvant chemoradiation population, so within an MSS patient, [who are] again, [our] more common patients? How do we approach that? That is where true multimodality patient care comes into play.

You’re asking exactly the questions that need to be asked. Immunotherapy [research is] super exciting stuff. As we all know, a few years ago [this work has been recognized with] the Nobel Prize and it has [led to] a sea change. Single checkpoint inhibitors haven’t been that useful in MSS colon cancer, but [there have been] really exciting data that we had the good fortune of participating in and have also been presented at the ASCO and ESMO [meetings]. Hopefully, [those data] will come out in a publication very soon, but they are showing that if you use potent checkpoint inhibitors together—for instance, an Fc-enhanced CTLA-4 antibody with a PD-1 antibody—it has about a 25% response rate in MSS colon cancer. [That said,] it's early days. A randomized phase 2 study of those two agents has just finished accrual. As such, we’re going to get the randomized phase 2 data, and hopefully that would mean that we can get [more information on] this therapy in [those with] heavily metastatic disease. We’ve already seen that subsets of the patients within the MSS population respond better. For example, patients who have liver metastases have a lower response rate to this checkpoint combination than [those who] have lung metastases, for instance.

As you rightly said, the clinical observations are actually trumpeting a little bit on biology. For IO therapy, specifically, biological models are very, very difficult because when you’re doing in vivo models in mice, you really cannot use human tumors in those mice because they have to be immune-competent mice. As such, the IO models in mice are not very well translated into humans so we have limitations preclinically there. However, for instance, this combination therapy is really an amazing advance because single checkpoint [inhibition] wasn’t working—even the first generation of CTLA-4 antibodies had limited activity. But [by] enhancing some of these checkpoints, you just see that a subset of those patients, specifically certain organ types where the colorectal cancer metastasized have higher response rates, and we don’t actually know what their overall survival is because the patients are still being followed. So, I would count that as a major advance, but not completely satisfactory. But if you take that and you use it in earlier phases, you can probably expect much, much more benefit for patients.

The key question would be: How do we move this immune therapy up front? Also, what kind of patients should we select? All of that [information] is coming. Then, the other [questions that are raised are,] how do you enhance these immune therapies? Can we add a third immune therapy? Should we add chemotherapy to that? But frankly, when I joined [the] oncology [field], I was hoping to ride a wave of science—and boy, have we been lucky. From the time I started my career 20 years ago in GI oncology, I remember we only had 5-fluorouracil. Basically, that’s all we had. Now, even with limited advances in what we do, [we’re moving forward,] so I’m very optimistic.

To answer the other part of your question, how do we make more advances and learn biology? I’m a big believer that you have to get the phenotype first. I mean, we can study the biology, which is very interesting and all of that, but [if] we have the clinical observation of a phenotype, then it’s really beautiful. Then we can take the biology, take five people who responded, [for example,] and really do a very magical thing from sample collection to really dissect out science much faster than just doing preclinical work all the time and trying to figure this out from the other end. As such, we’re really lucky that the gastroenterologists, like Toufic, can work with us, get us the samples, and [we can then] work together to dissect [this information] and really move [these approaches] earlier on to make these diseases, hopefully, curable, which is really difficult right now.

In this episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts discuss the potential benefits of utilizing immunotherapy approaches earlier on in the disease course.

Experts discuss the understanding that is needed to develop effective early detection methods and move the needle forward. 

Assays for Early Detection and Prevention

, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, explain the challenges faced with preventing or detecting these cancers early and the understanding needed to develop effective early detection methods and move the needle forward.

In the context of looking at these multiomic assays with diagnostic imaging or endoscopic evaluation, where do you think we would [get] the most bang for our buck? [For example,] we have had some advances that we’ve made in colorectal cancer in terms of the adjuvant setting with some of these liquid biopsies. Where do you see that to be a good spot where we have probably the most data and we might actually [get] the most bang for our buck?

In terms of [getting] return on investment, maybe we can think about it as two main areas. One is the area of early detection, where you want to [get] bang for the buck in detecting colorectal [cancer] or any of these malignancies early. That’s one potential area that we could talk about. The other would be to [take those] who are already prone to cancer and use the assays to basically prevent cancers. [With that,] I’m separating them from a general population to a defined population.

For the general population, I think there’s a lot of effort going on in malignancies that are fairly common. When you’re approaching [this] population, you need to increase the sensitivity and specificity, but you also need to have a relatively common tumor in order to develop these assays so then you can test them. There are many approaches that are being used for that area. Companies like Grail, for instance, have [put] a lot of resources [into] developing liquid biopsy, if you want to call it that—they’re mostly methylation of DNA in the blood. They have [put] a lot of resources [into] actually differentiating cancer from “normals.” They have spent a lot of time and energy over the years in collecting thousands of samples from “normal” people, and also from those who had different kinds of cancers like colon cancer. [As such,] their assays are getting better in that area of just taking a person off the street and just doing an assay.

Once that particular assay technology becomes even better, then we have the chance of actually detecting something like colon cancer, and we all know that if we could detect it early, we could cure most of those patients. [We also] know that the current gold standard for detection is colonoscopy and that has been very good, but the uptake of colonoscopy is low. In Arizona, I think the latest data [indicate that approximately] 52% of eligible people get colonoscopies. We also have another problem with colonoscopy, which is that we have an epidemic of young people getting colon cancer, which is unexplained. That epidemic really makes it harder to deploy colonoscopies. Because these people now are getting metastatic colon cancer essentially at very early ages. My clinic, and I’m sure your clinic, is full of people who are between 25 and 40 [years] who [have] metastatic disease and this is an epidemic that the National Institutes of Health has deployed consensus panels. Right now, the consensus is that it’s not a genetic phenomenon; it’s an epigenetic phenomenon. There’s something in the environment or something else that’s causing this epidemic. So, because of all these situations, we really need a sensitive and specific test that can be deployed in a relatively affordable way in that realm.

Now, when it comes to potentially detecting cancers, how do we go about taking the approach in more defined populations? In gastrointestinal [GI] malignancies, I’m sure that the gastroenterologists have difficulty figuring out pancreas cancer, [for example.] Pancreas cancer is uniformly lethal whenever it’s detected with symptoms. So, is there a possibility of narrowing down this large population to people who have some risk factors? [For example,] one could argue [that] people who are smokers or who are diabetics [have] a higher incidence. [Then there are] people who have family histories—obviously, that’s a small number, but that would be an opportunity to deploy a certain kind of test in that population. [These are good examples of where] we [can] narrow things down from a very large population to a smaller population, and then try to develop the test and [evaluate] its sensitivity and specificity.

I don’t know if I answered the question totally, but this is a complex issue. We are making lots of advances, and really, the gamechanger for GI malignancies is going to be detecting these cancers earlier.

In this episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts explain the challenges faced with preventing or detecting these cancers early and the understanding needed to develop effective early detection methods and move the needle forward. 

Leveraging Immunotherapy in GI Malignancies: Assays for Early Detection and Prevention

Experts discuss the potential for early detection multiomic assays and the work that still needs to be done to encourage their widespread use.

Is Multicancer Early Detection Becoming a Reality?

, Toufic Kachaamy, MD, of City of Hope, Sunil Sharma, MD, of City of Hope, and Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, discuss the potential for early detection multiomic assays and the work that still needs to be done to encourage their widespread use.

Hi, this is Toufic Kachaamy. I am the chief of medicine and the director of gastroenterology at City of Hope in Phoenix, Arizona. I’m joined today by Sunil Sharma, MD, and Madappa Kundranda MD, PhD. Dr Sharma is a medical oncologist and a physician-scientist who specializes in treating gastrointestinal [GI], neuroendocrine, and rare tumors. His research interests include the development of novel early-phase clinical trials and discovery of novel anticancer therapies. He is a world-recognized leader in early-phase drug development and has been instrumental in advancing several drugs from preclinical evaluation through phase 1, 2, and 3, and in immunology. He is also on the scientific advisory board of many biotechnology companies and has an MBA from the University of Massachusetts Amherst. Dr Kundranda is the division chief of medical oncology at Banner MD Anderson Cancer Center, and he will be talking today about immunotherapy—especially in the nonmetastatic GI malignancies and the potential for endoscopic ablation as part of multimodality treatment. Thank you both for joining me today.

Dr Sharma, the first question I have for you pertains to where we’re going with early cancer detection. Do you believe that multicancer early detection is becoming a reality? Will that lead to cancer stages shifting, with more patients diagnosed earlier [prompting us] to figure out how to treat them earlier?

Yes, thank you for the question. It is really an exciting time in [the realm of] cancer biomarkers, where a lot of effort is being put into detecting cancers early. As you all know, once the cancer is late stage it is really difficult to eradicate [it]. There are many different groups around the world that are working on [developing] more sensitive assays that can detect cancers early. I believe that as these assays improve, [they] will be a real game changer for GI malignancies. The reason I say that is because a lot of these assays in the past that have been used to detect cancers early have been used in slow-growing cancers, like prostate cancers. When you use these assays in those malignancies, you risk this phenomenon called “lead-time bias,” which means that you can detect the cancer early, but it doesn’t really help the patient because detecting the cancer early just simply leads to more unnecessary therapy sometimes because the natural history of those small, slow-growing cancers is so slow. That is not the case with GI cancers. As we all know, most of the GI cancers are aggressive. Pancreatic cancer is the most one of the most aggressive and highly lethal malignancies; colon cancer is the same, and even gallbladder and cholangiocarcinomas are fairly aggressive. As such, it’s a really important [advance] if we could [detect those malignancies] early. In general, philosophically, the lead-time bias would not be a huge concern in my estimation, because the natural history of the disease is so fast. So, that’s one point [I want to make].

The second point on these early detection, multiomic-type assays that are being deployed currently, is that the sensitivity and specificity [of these tests] are not quite there at the moment, but [what we’re seeing is] still pretty darn good. What has happened is that some of the assays that are currently being sold are decent in terms of sensitivity and specificity, but when you want to deploy these assays on a generalized population, you have to have significantly higher sensitivity and specificity and they obviously have to be affordable. So, currently, those 2 things are not quite [where we need them to be], but they’re getting there. There’s a huge amount of effort [that is being made with] this.

The third point I would make is that there has been a lot of recently published research [suggesting] that when you combine these approaches, [so] multiomic-type assays with clinical imaging or other kinds of methodologies, you can increase the sensitivity and specificity to really narrow down that population that you can then help. One example of that would be if you could combine endoscopic observations, for instance, with a multiomic assay—that would improve sensitivity and specificity, so that’s one possibility. The other possibility is combining radiologic [approaches] with [a multiomic] technique. My final thought would be if you could take a high-risk population where you define [what] “high risk” [is] and then use these assays. Then, you would have much more confidence in the moment, and you could narrow [things] down that way. So, those are my thoughts on that and the changing landscape.

You hit on 3 key things [about these assays. You mentioned] making sure [that they are] available to the general public and that it’s not just the lead-time bias that we’re looking at, but that we’re truly making a change in terms of the stage shifting per se. GI malignancies are so heterogeneous. When we think about breast or lung cancers, [they] are heterogeneous in [their] own way, but GI [malignancies] cannot be more heterogeneous than what we deal with in [terms] of management, treatment, and the like.

In this episode of OncChats: Leveraging Immunotherapy in GI Malignancies, experts discuss the potential for early detection multiomic assays and the work that still needs to be done to encourage their widespread use.

Sunil Sharma, MD

Articles

Leveraging Immunotherapy in GI Malignancies: Looking to the Future

Leveraging Immunotherapy in GI Malignancies: Research, Including Organoids and Ablation

Leveraging Immunotherapy in GI Malignancies: A Shift in Drug Discovery

Leveraging Immunotherapy in GI Malignancies: Assays for Early Detection and Prevention

Leveraging Immunotherapy in GI Malignancies: Is Multicancer Early Detection Becoming a Reality?