TARGETED ONCOLOGY THERAPIES – Harnessing Nature’s “Cues” to Selectively Activate the Immune System to Attack Cancer
A PATH TOWARD MORE EFFECTIVE, TARGETED ONCOLOGY THERAPIES
Cancer research has advanced considerably throughout the past 3 decades in search of more targeted therapies designed to provide improved patient benefit with long-term efficacy and reduced toxicity.
A recent and important breakthrough in the fight against cancer has been the emergence of immunotherapies, a variety of approaches designed to engage and restore the heavy artillery of a patient’s immune system to attack and destroy cancer cells.1-3
An early entrant and long-studied approach that has been in development for a few decades are the so-called immunotoxin therapies.2,3 Immunotoxins are bispecific molecules with two anchoring moieties – one is a structure that binds to a protein present on cancer cells, and the other is a “toxin” delivered to the cancer cells to kill them
One of the earliest examples of immunotoxin therapies is an antibody-drug conjugate (ADC) in which a cancer-targeting antibody is joined (conjugated) to a chemotherapy toxin.3-5 With the ADC antibody helping direct the chemotherapy toxin to cancer cells, researchers found that it was possible to use more potent chemotherapy agents than with more traditional systemic delivery, and this often resulted in fewer side effects. In addition to ADCs, this promising bispecific strategy also has been used in other ways to help increase the effectiveness of a treatment while at the same time limiting its side effects.
Another example of such conjugated molecules includes interleukin-2 (IL-2) based bispecifics, designed to deliver this highly potent immunostimulant molecule to activate an immune response against cancer.6-8 IL-2 is expressed throughout the body in a highly controlled and regulated manner and plays key roles modulating immune functions, including its ability to stimulate and activate T cells against cancer. Systemic IL-2 therapy was one of the earliest immunotherapy treatments that provided durable responses for cancer patients. However, delivery of systemic IL-2 has had very limited clinical success due to severe adverse effects and toxicity caused by the ubiquitous binding of IL-2 to receptors throughout the body, leading to death in some patients.7,8 The bispecific approach has helped ameliorate some of the side effects of systemic IL-2 treatment by biasing the delivery of IL-2 directly to cancer cells.6-8,10 Again, however, because IL-2 indiscriminately binds even at suboptimal therapeutic doses to any cell possessing an IL-2 receptor, these therapies have shown low tolerability and limited therapeutic responses to date. This brings a significant need for improved IL-2-based therapeutic options.
The two main limitations of IL-2 targeting therapies, which can in part explain low overall therapeutic response rates, are 1) they rely on the presence of tumor-specific T cells at the site of the tumor to be effective, and 2) there is a very small therapeutic window for natural IL-2 to have a desired clinical effect before treatment-limiting side effects emerge. There are on average 10-20 million unique T cell receptors, or unique immune system “addresses,” in our body that can specifically respond to a particular pathogenic challenge or disease. Even in sufficient numbers, disease or cancer-specific T cells of interest are not always present in the area around a tumor (the “tumor microenvironment”). This is particularly evident in “cold” tumors, where the amount of T cells in the tumor microenvironment is highly limited.10
One aim of the evolving field of immuno-oncology therapy is to amplify the immune response against cancer, but in a cancer-relevant and specific manner to marshal the patient’s immune system to actively attack the cancer of interest. As a result, a new class of synthetic biologic drugs have been engineered by Cue Biopharma and designed to leverage the beneficial effect of IL-2 to selectively stimulate the proliferation and cytotoxic activity of disease-relevant T cells against cancer. These targeted therapeutics, which are infused directly in the patient’s body, dynamically harness the patient’s own immune system to fight cancer. In essence, Cue Biopharma’s treatments mimic the natural process of immune recognition to activate T cells against specific disease targets such as cancer cells that can otherwise evade immune detection.
REVERSE-ENGINEERING THE NATURAL “CUES” OR SIGNALS TO HARNESS THE IMMUNE RESPONSE AGAINST CANCER
Cue Biopharma’s approach has been to reverse engineer the process of how T cells become activated during an immune response. Similar to how immunotoxins have an anchoring or an “address” moiety that binds to a specific cancer to deliver the toxin to a specific tissue, Cue Biopharma’s biologics are designed to preferentially engage tumor-specific T cells by taking advantage of the selectivity that already exists in nature, through targeting the specificity of T cell receptors for engagement of tumor-specific T cells.
Cue Biopharma’s Immuno-STAT(TM) (Selective Targeting and Alteration of T cells) platform creates stable, off-the-shelf molecules, referred to as Immuno-STATs, which have been engineered to mimic the natural mechanism that antigen-presenting cells (APCs) use to engage T cells during an immune response. Immuno-STATs do this through simultaneous presentation of two different signals or “cues” that lead to selective T cell activation against the disease target of choice.11-18
Signal No. 1 – Targeting Cancer- Relevant T Cells for Selectivity & Specificity
In nature, when specialized immune cells called APCs encounter a foreign protein in the body (eg, a virus or bacteria), their role is to engulf it and break down the proteins into small peptide fragments. The APCs then present the peptide fragments on their cell surface through a complex called the major histocompatibility complex (MHC). This MHC-peptide complex has a very specific three-dimensional configuration and will only bind to a T cell having a receptor (a “T cell receptor” or “TCR”) that has a matching three-dimensional configuration. The TCRs of the human immune system have millions of different three-dimensional configurations, and this “specificity” is the key to the immune system engaging only the population of T cells that will respond to the specific foreign protein encountered by the APC.
This binding of an MHC-peptide complex to a matching TCR is the first signal (Signal No. 1) that is required in order to activate the population of target T cells within the human immune system.
Cue Biopharma scientists have been able to create a stable, synthetic MHC-peptide complex that presents a tumor peptide of interest in the correct three-dimensional configuration to matching, target TCRs. The target TCR specifically recognizes and binds to the MHC-peptide complex in Cue Biopharma’s Immuno-STATs, thereby providing the same Signal No. 1 to the T cell. As in nature, this binding is the first step leading to T cell activation.
Signal No. 2 – Activating the Target T Cells to Amplify Anti-Cancer Activity
In nature, when an MHC-peptide complex binds to its matching TCR providing Signal No. 1, the T cell is primed to be activated through a second signal (Signal No. 2) referred to as a “co-stimulatory” signal. Co-stimulatory Signal No. 2 often consists of the key immune-regulatory signal, IL-2, which activates and amplifies the activity of the engaged T cell population and selectively converts these tumor-specific T cells into the CD8+ cytotoxic T cells that are the most relevant cells to promote destruction of cancer cells.
In essence, and as shown in Figure 1, the design of the Immuno-STAT molecule provides the targeting moiety through the MHC-peptide complex providing Signal No. 1, and also induces activation of targeted T cells through IL-2 providing Signal No. 2 . The Immuno-STAT is constructed upon a portion of a human antibody (the “Fc portion”) that serves as the molecule’s backbone and provides manufacturability and structural stability.
Through this combined signal approach, we believe Cue Biopharma has realized the promise of immunotherapy in cancer by targeting and activating cancer-relevant T cells directly in the patient’s body without the unwanted side-effects associated with other immunotherapy approaches, including IL-2 therapy.
IL-2 ENGINEERING FOR PREFERENTIAL ACTIVATION OF TUMOR SPECIFIC CD8+ CYTOTOXIC T CELLS IN CUE BIOPHARMA’S IMMUNO-STAT BIOLOGICS
CD8+ T cells are a significant cellular subset for anti-cancer responses and as such, IL-2-based therapeutics in development aim to activate the relevant members of this cell population to ensure effective cancer killing with an attractive tolerability profile. On the other hand, regulatory CD4+ T cells, also called Tregs, play more of a suppressive role in the immune response, and if activated, could dampen the benefit of CD8+ T cell activation. IL-2 activates T cells, both CD8+ as well as CD4+, especially Tregs, through its interaction with different subunits of the
IL-2 receptor in T cells (alpha, beta and gamma). IL-2 receptors have a wide natural range in binding affinities.15-18 The high-affinity IL-2 receptor, highly expressed on Tregs, is composed of all three subunits. Conversely, most CD8+ effector cytotoxic T cells express intermediate affinity beta-gamma subunits of the IL-2 receptor. This means that wild-type, or natural, IL-2 is more likely to bind and activate Tregs over the cytotoxic CD8+ T cells that are best at destroying target cancer cells.
Cue Biopharma’s IL-2 Molecules Are Engineered With Two Modifications That Maximize Activation of Tumor- Specific CD8+ T Cells & Minimize Off-Target Binding14-15
First, the IL-2 has been engineered to abrogate binding to the alpha subunit required for Treg engagement and activation, thereby minimizing the bias for regulatory T cell activation. Accordingly, the predominant effect of IL-2 binding by Immuno-STATs is the activation of cytotoxic CD8+ T cells.
Second, the IL-2 has been modified to attenuate, ie, lessen, the binding affinity to the beta subunit of the IL-2 receptor in order to ensure the activity of IL-2 is most favored to those T cells engaged with the Immuno-STAT molecule through Signal No. 1.
Both of these modifications to IL-2 enable the binding kinetics to be optimized for selective activation of only disease relevant T cells, harnessing the cooperative nature of T cell signaling (Figure 2). Therefore, Immuno-STAT therapeutics are both mimicking and improving the natural T cell activation response using a stable, synthetic off-the-shelf biologic drug.
OBSERVED INITIAL CLINICAL RESPONSE AS MONOTHERAPY
To date, Cue Biopharma’s lead drug product candidate, CUE-101, has demonstrated promising clinical results as a monotherapy, without dose-limiting toxicities, in a Phase 1 dose escalation trial. The ongoing clinical trial is testing CUE-101 as a second line and beyond treatment for human papilloma virus positive recurrent/metastatic head and neck squamous cell carcinoma (HPV+ R/M HNSCC). In this highly pretreated and resistant patient population, clinical activity has been observed, including a confirmed partial response with an approximate 50% tumor reduction and six stable disease responses, as of June 2021– a rarity for the immuno-oncology space in which very few immunotherapies show single-agent clinical benefit.
CUE-101, which is designed to activate and expand tumor-specific T cells that target HPV16-driven malignancies, incorporates the HLA-A*0201 allele bound to an epitope from the HPV16+ E7 protein (E711-20) to provide Signal No. 1 (Figure 3).11,14-18
The observed clinical activity of CUE-101 as monotherapy establishes initial proof of concept for the clinical potential of Cue Biopharma’s CUE-100 series of IL-2 based biologics for the treatment of cancer.
Given the targeted delivery of IL-2 and activation of tumor-specific T cells, Cue Biopharma’s approach has the potential to dose higher concentrations of IL-2 than the systemic IL-2 therapies available today. Cue Biopharma’s Immuno-STATs thus have the potential to engage tumor-specific T cells and provide anti-cancer efficacy without causing severe, systemic toxicity.
Additionally, the Company is advancing CUE-101 through a Phase 1 dose escalation trial in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab (KEYTRUDA®), as first-line treatment in the same patient population. Preclinical studies demonstrated the combination of CUE-101 and an anti-PD-1 checkpoint inhibitor appear synergistic by significantly extending survival in mouse models of HPV E7-driven cancers.
UNIQUE PLATFORM WITH PROMISING THERAPEUTIC POTENTIAL
In summary, the key differentiators of Cue Biopharma’s Immuno-STAT biologics from other IL-2-based therapeutics in development include the following:
Tumor Specificity: Due to the unique engineered MHC component for the presentation of tumor specific peptides, Cue Biopharma’s Immuno-STAT biologics can selectively activate cancer-specific T cells and turn them into cytotoxic T cells that can seek out and destroy cancer cells.
Selective Activation of CD8+ Cytotoxic T Cells: Due to the careful engineering of the IL-2 molecule, Cue Biopharma’s Immuno-STAT biologics are biased toward activation of effector cytotoxic T cells and avoid broad activation of Tregs.
Larger Therapeutic Window for IL-2 Effectiveness: Through additional modifications to the IL-2 molecules in Immuno-STATs, including lowering their binding efficiency for T cells, the Cue Biopharma team has greatly reduced the toxicities seen with other IL-2-based therapies. In clinical testing to date, CUE-101 has yet to show dose-limiting toxicities in dose escalation while already showing rare monotherapy clinical activity, suggesting these modifications are having their predicted effect.
As such, the key benefit of Cue Biopharma’s Immuno-STAT biologics is that they do not only diminish the indiscriminate IL-2 binding that leads to high toxicity, but they also favor the activation of cancer-specific cytotoxic T cells, which should result in increased efficacy without known IL-2-related safety concerns. Immuno-STATs offer the promise of providing targeted therapies for cancers with the potential for higher efficacy while avoiding the negative side effects of global systemic approaches.
Cue Biopharma’s molecules also present advantages over other tumor-specific immuno-therapies in development, such as CAR-T (chimeric antigen receptor T cells) or TCR-T therapies, because they do not require ex vivo manipulation.
Overall, given its unique mechanism of action by leveraging the natural immune response to exploit the specificity of T cells, its initial clinical efficacy as a monotherapy, and reduced toxicity, Cue Biopharma’s therapies represent a true breakthrough in cancer immunotherapy treatment, with potential to provide new life-saving options for multiple cancers.
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- Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies. Clin Cancer Res. 2020;26(8):1953-1964.
- Poster: Quayle SN, Girgis N, Thapa DR, Moniz, R, Vakkasoglu, Merazga, Z, Zhang, C, Saggu ,G, Histed, A, Diaz, F, Yeung, K, Bautista, W, Ryabin, J, Witt, L, Soriano, J, Low, S, Ross, J, Seidel, R, CEmerski, S, Suri, A. Immuno-STAT™ (Selective Targeting and Alteration of T cells) Platform: Targeting Tumor Heterogeneity and Tumor Escape Mechanisms. Poster presented at: Frontiers in Cancer Immunotherapy Conference; May, 2021. Virtual.
- Presentation: Cemerski, S. Directly Targeting Autoantigen-Specific T cells with Immuno-STATs. Oral presentation at: Antigen Specific Immune Tolerance Digital Summit; January 2021. Virtual.
- Poster: Histed A., Girgis N., Moreta M., Soriano J., Witt L., Merazga Z., Diaz F., Zhao F., Kemp M., Ruthardt P., Thapa D., Suri A., Seidel R., Pienta K., Simcox. M., Quayle S., Ross J., Cemerski S. CUE-100 series Immuno-STATs from concept to the clinic: Leveraging protein engineering to stimulate and selectively deliver affinity attenuated IL-2 to antigen-specific T cells. Poster presented at: Society for Immunotherapy of Cancer Annual Meeting; November 2020. Virtual.
- Poster: Zeigler S , Woodham A , Li M , Zeyang L , Kolifrath S, Cheloha R, Rashidian M, Chaparro R, Seidel R, Dearling J, Mesyngier M, O’Connor K, Celikgil A, Duddempudi P, Packard A, Garforth S, Goldstein H, Ploegh H, Almo S. Immuno-STATs: Leveraging protein engineering to expand and track antigen-specific T cells in vivo. Poster presented at: Society for Immunotherapy of Cancer Annual Meeting; November 2020. Virtual.
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- Pai S, Adkins D, Wirth L, et al. A phase 1 trial of CUE-101 a novel HPV16 E7-pHLA-IL2-Fc fusion protein in patients with recurrent/metastatic HPV16+ head and neck cancer Journal for ImmunoTherapy of Cancer 2020;8: doi: 10.1136/jitc-2020-SITC2020.0354.
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Dan Passeri is Chief Executive Officer of Cue Biopharma, and is a seasoned biotechnology executive with over 20 years of experience managing drug discovery and development programs as well as business development activities on behalf of publicly traded companies, with deep experience in both oncology and strategic partnership generation. Prior to joining Cue Biopharma, he served as President and Chief Executive Officer as well as Vice Chairman of the Board of Curis, Inc. Prior to joining Curis, he was employed by GeneLogic Inc., most recently as Senior Vice President, Corporate Development and Strategic Planning. Prior to his work at GeneLogic, he served as Director of Technology Management at Boehringer Mannheim. He earned his JD from the National Law Center at George Washington University, his MSc in Biotechnology from the Imperial College of Science, Technology, and Medicine at the University of London, and his BS in Biology from Northeastern University.
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