Targeted Immune System Activation: A Paradigm Shift in Immuno-oncology

Targeted Immune System Activation: A Paradigm Shift in Immuno-oncology

January 04, 2023PAO-12-022-CL-01

The field of immuno-oncology has advanced significantly, but significant challenges remain to achieving its full potential. Checkpoint inhibitors only work for about one-fifth of patients. The key, according to Dan Passeri, M.Sc., J.D., Chief Executive Officer of Cue Biopharma, is selective activation of the immune system in conjunction with checkpoint disruption. Cue Biopharma has developed a platform technology for the engineering of biologics that, when constructed with a cancer-specific peptide, can target specific cancer cells to avoid any undesired side effects. In this Q&A, Passeri discusses the state of immuno-oncology and Cue Biopharma’s technology with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): To start, can you share some historical background on the genesis of Cue Biopharma?

Dan Passeri (DP): The company was founded in 2015 on the basis of technology developed in the protein engineering lab of Dr. Steven Almo, who is the Chairman of the Biochemistry Department at the Albert Einstein College of Medicine. The basic concept is to engineer proteins that emulate the selective immune responses that occur within the body in response to exposure to various pathogenic challenges.

DA: Why was the approach to engineer proteins that emulate those signals rather than working with the signaling molecules themselves in a more conventional manner?

DP: Steve Almo is not an immunologist, nor is he an oncologist. That turned out to be fortuitous, because he had no preconceived notions of how to address cancer. An oncologist will look at the tumor microenvironment and the off-switches or checkpoints present there that create challenges for the immune system. An immunologist, meanwhile, will look at the problem with a different biased set of optics. As a protein engineer, Steve simply asked the question: How does nature activate a T cell?

That is done through a specialized system of antigen-presenting cells (APCs). Dendritic cells are one type of APCs. They are specialized cells that navigate through the body to find foreign proteins, engulf them, break them down, and then present fragments of them on specialized scaffolds referred to as major histocompatibility complexes (MHCs). T cell receptors (TCRs) can then bind to those protein fragments because every T cell has one TCR on its surface that recognizes the shape of a particular protein. If activated in the appropriate manner, the T cell will seek a cell that presents that protein shape on its surface and destroy it.

That is a great way to address viral and bacterial infections, but it must be implemented in an exquisitely controlled manner. If T cells kill indiscriminately, for example kill cells or tissues belonging to the self, autoimmune diseases result. Steve Almo’s group looked at how nature has designed that interface between APCs and T cells. They looked at the signals involved and tried to reduce them down to the key signals essential to activating T cells.

They found two key components. One is the presentation of the epitope on the MHC scaffold that allows a TCR to bind to it. That is the identity or address, telling the T cell it has found what it is looking for. The second is a corresponding adjacent signal –– signal 2 –– that tells the T cell to activate itself and seek and destroy its target cell. Together, they comprise a command-and-control set of signals. On the basis of this information, Almo and his colleagues Ron Seidel and Rudy Chaparro, designed a protein structure that presents a particular peptide of choice — a piece of a protein of interest, which in this case is any protein that is specific to cancer. The protein finds a T cell that targets the cancer and then delivers an immunostimulant molecule, interleukin 2 (IL-2), only to that T cell in order to activate it. Thus, by injecting this protein into the patient, a population of activated T cells against the cancer of interest is created in the patient’s body.

The overall concept, therefore, is to design proteins that engage the immune system in a very targeted, selective manner. Through that specificity, we can either activate the immune system to attack a particular cell type, such as a given cancer, or deactivate T cells to try to shut off autoimmune disease.

DA: Can you give me a brief overview of the engineering science underlying the creation of Cue Biopharma’s pipeline and platforms?

DP: There is tremendous experience in the biologics field with respect to making antibodies. Antibodies are proteins that exist in the body and, as such, should not be immunogenic, i.e., not induce an immune reaction against the protein therapeutic itself. They are manufactured cost-effectively using standard processes and platform technologies.

The fundamental protein biologics that Cue Biopharma has engineered are designed to have all the components that exist in human biology and to look very much like an antibody. As a result, the fusion protein has proper folding and is highly stable. It is built on an Fc fragment and has heavy and light chains. Two MHC scaffolds on top of the Fc fragment hold a chosen peptide unit that is presented to the appropriate TCR. IL-2 molecules are also part of the fusion protein, two on each side, in the case of our lead clinical asset CUE-101, exemplary of the IL-2–based CUE-100 series.

Overall, the protein is a symmetrical molecule that binds to a T cell surface membrane by engaging the TCR. With two MHCs engaging two TCRs, TCR dimerization is fostered to create signal 1. The IL-2s then generate signal 2, which activates the targeted T cell. The lengths of the linkers connecting the IL-2 molecules to the protein scaffold were optimized to enable maximal signaling. Overall, therefore, the protein is designed and optimized to generate both signal 1 and signal 2 for T cell activation and proliferation. The generated T cells are transcriptionally transformed into cytolytic killer T cells.

Because the protein is much like an antibody, it is produced using similar technologies and with a similar cost of goods. A standard process has been developed that can be used for different versions of the protein, with only the nine amino acid sequence within the MHC pocket needing to be changed.

I should also note that we have taken into consideration the existence of different allele frequencies in different populations. CUE-101 is HLA A*02, which is appropriate for approximately 40–50% of the U.S. and European populations, as well as a significant percentage globally. In Asia, A*11 and A*24 are more prevalent. We have also made those constructs. So, we have a number of allelic structures that we have made and are developing the capacity to cover a higher percentage of the global patient population. 

DA: Could you walk me through how this approach led to the development of Cue Biopharma’s lead candidate CUE-101?

DP: Many immunotherapies are based on the concept of checkpoint inhibition. These drugs interfere with checkpoints, such as CTLA-4, PD-L1/PD-1, Tim-3, VISTA, and so on, which are all basically off switches that the body uses to prevent immune cells from attacking the body’s own cells. Checkpoints, therefore, are the mechanisms by which the body protects itself from inducing autoimmune diseases. T cells are extraordinarily potent killer cells, and if they are not controlled properly, they can cause a lot of collateral damage.

Cancer cells are derived from normal cells but no longer listen to proper instructions. They hijack human biological signaling, including using checkpoints to evade the immune system. This fact has largely driven the immuno-oncology field with the hope that, if properly activated, a patient’s own immune system may be able to fight cancer without the need for toxic chemotherapy agents and the many deleterious side effects they cause.

Some companies have been trying to deploy the cytokine IL-2 in therapeutics, which has been approved as the product Proleukin® for the treatment of two conditions involving immunologically active cancers (i.e., melanoma and renal cancer). IL-2 is interesting because it is a known and well-characterized activator of T cells but is used by the human body under exquisite control. Only in the appropriate context, for example within an area of inflammation, will IL-2 be transcribed or produced to further the activation of T cells with engaged TCRs. The problem with the existing IL-2 drug and analogous drug candidates is that IL-2 is delivered systemically and thus indiscriminately, enabling binding to all IL-2 receptors to which it is exposed. As a result, collateral side effects typically manifest before any therapeutic benefit is observed.

At the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting in early November 2022, Cue Biopharma released data that demonstrated the effective use of IL-2 in a controlled manner. We were able to identify a range of doses defining a therapeutic window for our candidate CUE-101, enabling an increase in the relevant T cell populations that are specific to the cancer cells without having unwanted side effects resulting from undesired cell activations.

Our success derives from the manner in which the protein has been engineered. It engages specific T cells that target a protein present on the targeted cancer cells. Specifically, CUE-101 targets a human papilloma virus (HPV) protein segment called E7 (11–20) — a nine amino acid sequence — which is presented to T cells on an MHC with a modified IL-2 that binds to the IL-2 receptor primarily through the avidity of the entire CUE-101 molecule rather through affinity of IL-2 binding to its receptor alone. This approach leads to a collective binding attraction, which creates multiple binding units that are difficult to disassociate (i.e., two MHC-peptide/TCR binding units along with four discrete IL-2/receptors).

By infusing a protein that selectively activates only cancer-relevant T cells, it is possible to achieve a therapeutic window, with patients able to tolerate the drug at relatively high doses and at a range known to result in T cell activation. When used in combination with checkpoint inhibitors, a significant mechanistic benefit has been observed, with T cell populations increasing and attacking cancer cells after the checkpoint activity has been shut down. The data are early, but they suggest that the number of patients responding to Keytruda® (pembrolizumab, Merck), which generally has a 20% overall response rate, is doubled when this checkpoint inhibitor is administered in combination with CUE-101.

These early results suggest that we have potentially identified a breakthrough approach to practicing immuno-oncology with a new way to stimulate the immune system in a cancer-specific manner. We may be onto something profound in terms of transforming the space — reactivating the immune system so that it recognizes cancerous cells as foreign and harmful.

DA: How generalizable do you anticipate that your approach may be within the full spectrum of cancers?

DP: Theoretically, this approach should work for any cancer in which the cancer cell expresses a protein that is specific only to those cells and not present on the surfaces of normal tissues. The cancer epitope must be known so that IL-2 can be targeted to the specific T cell relevant to that cancer. One additional benefit of using this targeted approach is that much higher doses can be administered. With CUE-101, patients are able to tolerate much higher doses than can be given with indiscriminate IL-2 therapies.

Looking into the future, we believe that this approach has even wider applicability, specifically for personalized immunotherapy. We envision that, as capabilities for tumor sequencing and neoantigen identification for specific patient tumors advance, personalized, patient-specific IL-2 therapies can be developed.

DA: What is the relationship between CUE-101 and the other candidates in your pipeline? Are they analogous but with different epitopes?

DP: The elegant part of this approach and the way the platform is structured and designed is that CUE-101 is the first representative therapeutic molecule for the CUE-100 series, which is our series of IL-2–based therapeutics. We can also use IL-15 for instance. Within the CUE-100 series, CUE-101 is different from CUE-102 only in a nine–amino acid sequence that’s held in the MHC pocket; greater than 99% of the molecule is exactly the same framework from one drug to the next.

This difference relates to the epitope presented to the TCRs for recognition and binding, which is a very important feature. But the way the system is designed, it possesses cassette-like modularity, allowing different epitopes to be plugged in to target different T cells. Consequently, each drug is viewed as an analogue of the first one.

When we filed for the IND for CUE-102, we therefore made the case to the FDA that this second candidate is in essence the same as CUE-101, except for the nine amino acid sequence that targets a different T cell. That premise was accepted by the FDA, allowing us to go forward without having to repeat preclinical animal toxicity studies. We were also allowed to use the tolerability profile of our dose-escalation study of CUE-101 and truncate the dose escalation required for CUE-102. That is a profound accomplishment, as it indicates that this platform is modular and fundamentally de-risked.

DA: Assuming things continue to go well and that you ultimately find success with these therapies, how do you see them fitting into the landscape of cancer treatments? How might they function as part of a more complex treatment strategy?

DP: I think it’s important to emphasize where we are in the progression of the immuno-oncology field. A tremendous amount of capital has been invested in the overall immuno-oncology sector. There’s no doubt that checkpoints will remain a mainstay. They are essential because they’re turning off the defensive shield with which the tumors are trying to protect themselves from the patient’s immune system. The key is to then activate the immune system in a cancer-relevant manner so that the combination of drugs yields the desired effect. Attempts to date have been disappointing. Some suggestive data has been obtained, but nothing to date has defined a clear path forward. I see checkpoint inhibitors as equivalent to the Wright brothers’ first 30-second flight, which since has turned into the technology we have today. That’s what checkpoint inhibitors represent in the immunotherapy field, a glimpse of what is possible with further developments.

What we are learning to do at Cue Biopharma is enhance activity with specificity. We see CUE-101 as the beachhead –– we are establishing a foothold from which we can expand. We’re clearly showing that this drug appears to have a mechanism that is complementary to checkpoint inhibitors. If we can continue achieving success with this one indication, we can then branch into CUE-102 for Wilms’ Tumor 1 and eventually broader indications. We also have a KRAS program, for instance, and there are many other known antigens we can target. The key then will be to effectively scale the program in a highly productive manner.

I think the field itself is starting to recognize you cannot achieve therapeutic benefit and tolerability without specificity. They go hand in hand, and our competitive edge is the specificity that we’ve dialed in, that we’re delivering IL-2 only to targeted T cells.         

The future will be based on our ability to modulate a patient’s immune system in a tailored manner. With our approach, we activate only identified cancer-relevant T cells. In addition, we have the potential to do the converse — deactivate T cells associated with autoimmune diseases. We haven’t had the capital resources to build that platform out yet, but it has the same premise and promise. If we can identify known T cell populations that are relevant to autoimmune disease for which there is a checkpoint off-switch, then we can potentially shut them down and ameliorate autoimmune diseases. We are truly at the beginning stages of a new era in immune modulation as a therapeutic approach.

DA: Is there anything that you can preview for us about what the next year or two is going to bring to Cue Biopharma in terms of advancing your clinical and preclinical programs?

DP: As you know, the capital markets are highly distressed right now. Cue Biopharma is in a very good position because of the data presented at SITC. I think we are actually in the forefront with respect to providing a path forward for how to complement checkpoint inhibitors and expand the number of patients that will benefit from immunotherapy.

What is important is to continue with our first molecule to build up the patient numbers. To date, we have reported on the first 10 patients at 4 mg/kg. We want to expand to 20 patients and then define a registration path forward. We’re starting to get a lot of interest from the checkpoint inhibitor companies because of how complementary these data are, and we expect the momentum to continue to build.

Next, we need to demonstrate how modular this platform is with CUE-102. If we demonstrate clinical activity as a monotherapy in various solid tumors, that will be a significant development, because it will further de-risk and validate the platform’s modularity and that CUE-101 and CUE-102 operate via the same mechanism of action but target different T cell populations.

We have preclinical evidence for CUE-102 using human blood from cancer patients with Wilms’ Tumor 1. The drug ex vivo is able to engage the specific T cells that we’re targeting and cause them to proliferate. While that is outside the body, there is no reason similar activity shouldn’t occur inside the body. It is important to remember that the drug itself does absolutely nothing to the cancer cells per se (i.e., it is not cytotoxic to the cancer cells). What it does do is stimulate the patient’s own immune system to recognize cancer as foreign. The quality and type of data we are seeing is a profound development.

We also have a next-generation platform derivative, whereby this two-plasmid system fusion protein has a stabilized MHC pocket, even when it contains no peptide. Using this framework, it is possible to develop dedicated cell lines for each allele (A*02, A*11, A*24). The peptide can then be chemically attached to the framework. Such an approach provides greater efficiency and dramatic increases in productivity, because we can produce the protein in bulk and then attach different epitopes chemically. It also potentially makes the development of precision medicines economically feasible.

Going forward, we will continue the evolution of the platform to show modularity and demonstrate its broad reach and potential. We also need to scale in a strategically purposeful manner, because capital is not a trivial thing to come by today. The key will be to partner with pharmaceutical companies that understand the space well and are aligned with our vision. An important next step for us will be to systematically evaluate which pharmaceutical companies are in the forefront and understand the power and potential of our platform.

Ideally, we will form a strategic partnership in which we still retain significant upside of the platform. What we don’t want is to partner multiple programs to multiple companies. We want to find a strategic partner with an aligned vision of the platform’s potential, giving us the ability to evolve and develop the platform in a rigorous and systematic manner while enhancing productivity and scalability.

DA: What do you see down the road from a big-picture perspective as the ultimate impact of your technology and your approach to the treatment of cancer?

DP: We think we are on the verge of answering the fundamental question: How do you stimulate a patient’s immune system against cancer without all the unwanted side effects of indiscriminate activation? We are close to demonstrating that we have a platform that carries tremendous potential for selective activation against any epitope and that complements the mechanism of checkpoint blockage.

In the field of immuno-oncology in general, there is growing understanding of how to modulate a patient’s immune system in a manner that optimizes the anti-cancer effect. Checkpoint inhibitors have been shown to be very important, yet they still require activation of the immune system, which for patients with cancer is by default not occurring because the cancer is evading it.

Cue Biopharma’s technology makes it possible to activate the immune system in a dialed-in, selective manner and is providing additional understanding about which other mechanisms might be most synergistic or complementary. In addition to checkpoint inhibitors, other immune suppressive features that can be blocked will also benefit from use in combination with treatments that stimulate the immune system.

All of this expanding knowledge and the ongoing advances being made in the immuno-oncology sector will transform cancer therapy. We are currently in the midst of a paradigm shift in cancer therapy. Rather than treat patients with toxic chemotherapy agents to which most cancers eventually adapt, we will be training the immune system to selectively recognize cancer as foreign and attack tumor cells. Once T cells are activated and begin killing cancer cells, other antigens will be released by the tumors that will likely also be recognized as harmful and in need of destruction, furthering immune stimulation against the cancer. The immune system will then have memory and continue destroying cancer cells that are produced in the event of micrometastases, thereby extending life significantly and potentially eradicating the cancer completely. Eventually, with this type of treatment, cancer will potentially become a curable or at least a livable disease.

Furthermore, the same principle, except in reverse, will apply to autoimmune diseases. Instead of suppressing the entire immune system and leaving patients susceptible to cancers, infections, and so on, tailored therapies with activity against specific T cell populations or antibodies could address autoimmune diseases by shutting down the aberrant parts of the immune system. Such an approach would be yet another paradigm shift.

It is quite an exciting time to be involved in immuno-oncology and immune modulation itself. Not just Cue Biopharma, per se, but the field itself is on the cusp of some truly major breakthroughs.

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