Botensilimab: A Novel Anti-CTLA- 4 Therapy Effectively Treats Refractory Colorectal Cancers

Global Cancer Movement: Challenging the Status Quo in Colorectal Cancer by OncoDaily was held from December 6-8, 2024.

This three-day virtual event brought together a diverse range of experts, including leading oncologists, researchers, patients, advocates, and key figures from international health organizations. Together, they explored the current state of colorectal cancer, addressing both the challenges and opportunities in the fight against this prevalent disease. The event provides a platform for engaging discussions on the latest scientific research, breakthrough therapies, and global health strategies aimed at improving patient outcomes. It also focused on how to stimulate innovation in colorectal cancer care, enhance early detection, and ensure equitable access to treatment for all patients.

Dhan Chand, Vice President of Research at Agenus, shares pioneering insights from the inaugural Global Cancer Movement event, presented by OncoDaily. This virtual event, held from December 6-8, 2024, brought together leading experts to explore the transformative role of immunotherapy in treating microsatellite-stable (MSS) colorectal cancer, a condition that has traditionally been resistant to such therapies.

Dhan Chand, Ph.D., is Vice President of Research at Agenus, focusing on cancer immunology, immunotherapy, and cell and molecular biology. Previously, he served as a Graduate Research Assistant and Project Co-Leader in the Department of Cell and Systems Biology at the University of Toronto.

Thank you to the Global Cancer Movement organizers for the opportunity to present today. Over the past decade, we’ve witnessed immunotherapy emerge as arguably the most effective approach to treating cancer. By harnessing the power of the immune system, we’ve been able to put the words cure and cancer in the same sentence.

However, that is the story of a small subset of cancers, typically characterized as hot and immune responsive like melanoma. But in colorectal cancer, as Erica mentioned earlier, it’s the second leading cause of cancer mortality worldwide. Conventional immunotherapy has remained largely ineffective for the vast majority of patients.

But what if we can change that? What if we could transform these cold treatment refractory tumors into immunologically active or hot tumors, making them more responsive to immune attack? Today, I’ll share with you a novel therapeutic approach that we designed to do just that.

And that is Botensilimab, a multifunctional, FC-enhanced anti-CTLA-4 antibody that is showing unprecedented ability to drive clinical responses in these traditionally difficult to treat colorectal cancers. So before I dive in, these are my disclosures. I want to begin with a striking example.

A 40-year-old patient whose stage three microsatellite stable or MSS colon cancer showed a dramatic response to Botensilimab therapy just after just seven weeks of treatment. The patient, as you can see on the left, presented with an eight centimeter tumor. And after receiving just one dose of Botensilimab, or FC-enhanced anti-CTLA-4 antibody, and two doses of Balstilumab, or anti-PD-1 antibody that’s pharmacologically equivalent to approved PD-1s, you can see from the image on the right a remarkable transformation from a visible tumor mass to what appears to be a normal colonic mucosa.

Moreover, this patient was spared disfiguring surgery. Now, this is not an isolated case. In fact, this is the reality for scores of patients treated with Botensilimab thus far, and powerfully illustrates the potential of this approach.

Now, this audience needs no introduction to the magnitude of problem we’re facing globally. But let me frame some key issues here. Imagine being diagnosed with colorectal cancer today.

If you have microsatellite-stable colorectal cancer, as 95% of metastatic patients do, your treatment options remain largely unchanged for the past two decades. Despite some advancements, really and truly the current reality is sobering. Surgery in newly diagnosed stage 2-3 patients often results in poor quality of life, with organ loss and bowel and bladder dysfunction.

And for metastatic disease, the five-year survival rate is just 15% with current approaches. Perhaps most alarming is the concerning trend we’re seeing for increasing diagnosis in younger populations. So, why have immunotherapies that worked so well in other cancers, like melanoma, failed in MSS colorectal cancer?

Well, the fundamental challenge has been that these MSS tumors are immunologically cold. And what I mean by that is that they lack the immune cell infiltration needed for conventional therapies to work, such as CD8 T-effector cells. Instead, they’re infiltrated by regulatory T-cells and myeloid cells that actively suppress the immune response to cancer.

And also, by definition, microsatellite-stable tumors have a functional DNA mismatch repair system. So, in other words, they have a lower mutation rate and thus fewer neuroantigens, which leads to limited T-cell priming, defective antigen presentation, and eventually lack of tumor killing. Now, the consequences of these characteristics, particularly in the refractory setting, are poor response rates to immunotherapy, at least to the conventional approaches.

In fact, response rates to PD-1 or PD-L1 inhibition are near 0%. Even combinations of immunotherapy like ipinivo or dervalumab, so PD-1s and CTLA-4s, the conventional approaches, have shown limited efficacy and shorter progression-free survival. So, how do we overcome these challenges?

Well, Botensilimab was specifically designed to address these barriers by enhancing T-cell priming and essentially converting a cold tumor to a hot or more immune-responsive tumor. How is this achieved? Well, CTLA-4, as expressed on T-cells, plays a key role in regulating T-cell priming and activation by modulating the immune sign-off between T-cells expressing CTLA-4 and antigen-presenting cells.

But we discovered that blockade alone of CTLA-4 to promote T-cell priming was insufficient, but can be optimized by co-engaging activating FC receptors expressed on APCs, particularly FC-gamma-R receptor 3A. As such, we engineered Botensilimab to bind with high affinity to these activating FC-gamma receptors. So, this improved interaction via the FC enhances the quality of the immune sign-offs between CTLA-4-expressing T-cells and FC-gamma-receptor-expressing APCs or dendritic cells.

The consequence of this stronger interaction is stronger T-cell receptor signaling and a longer duration of T-cell receptor signaling, resulting in better T-cell priming, better T-cell activation, and better memory formation. This essentially leads to a more diversified T-cell response that can recognize the cancer. Secondly, by stimulating these activating FC-gamma receptors, Botensilimab enhances APC or myeloid activation, upregulating co-stimulatory molecules that further potentiate T-cell responsiveness.

Now, being able to activate the myeloid population, which by the way, are among the most dominant immune cell type in cold tumors, further remodels the tumor microenvironment to be more immune responsive. Thirdly, Botensilimab promotes FC-dependent depletion of immune-suppressive Tregs in the tumor, while sparing your peripheral Tregs or non-Treg cells. Tregs that express high levels of CTLA-4 are depleted, thus removing a key suppressive barrier and together with the T-cell priming that I mentioned earlier, enhances the CD8 effector to Treg ratio that favors anti-tumor immunity.

Now, lastly, I want to touch on safety because this has often been the Achilles heel of CTLA-4 therapy. To address this, we introduced a point mutation in the FC region of Botensilimab that eliminates some of the most difficult to treat adverse events, particularly those associated with complement fixation, such as hypophysitis. But we’ve also seen a reduction in other visceral toxicities as well, such as pneumonitis and hepatitis, and I’ll share some of that data with you.

Now, of course, the clinic is where we’ll see if these mechanisms I spoke about translate to efficacy. Focusing on the MSS-CRC cohort from our Phase 1 trial, these patients were heavily pretreated with a median of 3 prior lines of therapy and tumors with low neoantigen burden, that is, less than 10 mutations per megabase. Many were PD-L1 negative, so nothing really remarkable to suggest that they would be responsive to conventional checkpoint therapy.

But here, patients were treated with either 1 or 2 mg per kg of Botensilimab, or bot, every 6 weeks, and anti-PD-1, or balstilamab, otherwise known as bal, at 3 mg per kg every 2 weeks. And here, in this trial, patients without active liver meds, we observed a 23% response rate with a disease control rate of 73%, and the median duration of response not yet reached. In fact, this in itself is remarkable, but what you can see on the waterfall plot and in the spider plot shown below are the depth of responses and the durability of those responses.

In fact, early patients are only 2 years out. To put this into perspective, standard of care in this population has a response rate of anywhere from 2 to 7% and poor durability. Instead, with the combination of bot-bal, we’re seeing a median overall survival of 21.2 months, whereas current standard of care treatments typically show a median survival of 10 to 14 months, already a significant improvement over what’s currently available for these patients. Now, with regards to safety, looking across the larger phase 1 trial, grade 3 plus immune-mediated adverse events occurred in about 26% of patients, with most being limited to the GI tract, consistent with the class.

However, other visceral toxicities common with the class were rare, occurring in less than 2% of cases, and we hypothesize that this is due to the lack of complement binding that we specifically engineered into Botensilimab. So, despite enhancing function and efficacy, we did not amplify common immune-related adverse events, and more importantly, avoided some of the most difficult-to-treat ones that often limit the use of first-generation CTLA-4 therapies.

So, how does Botensilimab achieve these results, whereas conventional IO does not? Well, as I alluded to earlier, the power of Botensilimab lies in its ability to leverage mechanisms beyond that of conventional checkpoint blocking. Shown here in a T-cell APC co-culture assay, Botensilimab, shown in red, enhances T-cell priming, superior to that observed with conventional anti-CTLA-4 antibodies, or ipilimumab-like molecules, shown in black, both in terms of potency and the magnitude of response.

And that is because of the ability of Botensilimab to enhance the quality of the immune synapse between T-cells and APCs via that unique FC-enhanced region of the antibody. More importantly, given the importance of FC-gamma receptor co-engagement for the activity of anti-CTLA-4 therapy, you’ll notice that T-cell responses to Botensilimab are independent of FC-gamma receptor genotype, overcoming another limitation of conventional anti-CTLA-4 therapy. This enhanced T-cell priming is observed in patients treated with Botensilimab.

So this is data coming from the Phase I trial. Using T-cell receptor sequencing, we observed the ability of Botensilimab to reshape the T-cell repertoire, increasing both the number of T-cell clonotypes and, more importantly, driving expansion of new T-cell clones. In other words, Botensilimab is creating a more diversified T-cell response capable of recognizing these proliferative tumors.

In addition to T-cell priming, Botensilimab also enhanced the expansion of dendritic cells, an effect not observed with the conventional anti-CTLA-4 therapy, as shown on the left.

And looking further into the phenotype of these expanded cells, we observed that Botensilimab increased the activation of these cells, as observed by the upregulation of activation markers such as CD40, HLA-DR, and CD86, co-stimulatory molecules that, in turn, further enhances T-cell activation and effector function, again, an effect that was not seen with the conventional anti-CTLA-4 therapy. Even more remarkable is when we look at what’s happening in the patient’s tumors, Botensilimab reduces the frequency of suppressive intratumor regulatory T-cells, or Tregs, while simultaneously enhancing the infiltration of CD4 helper cells and CD8 T-cells.

This is crucial because it tips the balance from immune suppression to immune activation. This has been the promise of first-generation CTLA-4, but never fully realized clinically. We’re seeing this with Botensilimab.

And this remodeling of the tumor microenvironment from cold to hot, that tipping of the balance, is further evidenced by the significant increases in interferon gamma signaling and T-cell inflamed signatures that we observe in patients treated with Botensilimab. The very same markers that typically predict response to immunotherapy in hot tumors are being induced by Botensilimab in these cold tumors. We also see an upregulation of chemokines like CXCL9 and 10 and CCL5, all responsible for promoting the trafficking of T-cells and infiltration of those T-cells into the tumor microenvironment.

And just to show you what all this looks like, here is an example of a patient with MSS-CRC, where, as you can see on the left in the pretreatment biopsy, the tumor, as shown in yellow, has very few infiltrating CD8 T-cells, but lots of suppressive regulatory T-cells, as shown by the red dots. In fact, this would be a typical example of a cold, immune-excluded tumor. But on the right, in the post-treatment sample, you can see a significant infiltration of T-cells, expansion of CD8 T-cells, as seen by the purple dots, an absence of Tregs, and, of course, a shrinking tumor.

Basically, the mechanisms of action which I’ve described are being observed in patients treated with Botensilimab, turning these cold tumors into hot, immune-responsive tumors.

Now, I’m sure you agree that the responses we’re seeing with Botensilimab in the refractory setting is remarkable compared to currently approved therapy, but we can do better. And I couldn’t think of a better forum challenging the status quo to raise this call. The future of oncology demands that we shift our paradigm from cancer control to cancer cure.

And I hope I’ve convinced you of the power of harnessing the immune system to do so, particularly with Botensilimab. But to the clinicians and drug developers who are attending this conference, I implore you, champion immunotherapy not as a last resort, but as the first line of treatment for curative intent, especially in colorectal cancer. So, as I began with a provocative example demonstrating the power of Botensilimab in an MSS CRC patient, let me end with an equally provocative slide.

They say most people remember the first slide and the last slide, so here’s my last slide. A waterfall plot that actually looks like a waterfall. In the neoadjuvant setting, a trial championed by Dr. Pashtoon Kasi, where patients received one dose of Botensilimab followed by two doses of the anti-PD-1 antibody dostarlimab, demonstrated profound pathological responses, especially in the MSS setting. Some of you may be well aware that Dr. Myriam Chalabi at the NKI showed this in the more immune sensitive MSSI high setting. Now it’s becoming a reality in the MSS setting with Botensilimab, with many patients achieving complete pathological responses. This is what moving to earlier lines look like.

Giving the immune system a fighting chance and more time to work may lead to better outcomes. So with that, thank you. And I first want to acknowledge the patients and their families for participating in our trial, our clinical investigators, and of course the many, many individuals who made this work possible.

Thank you for having me.