HPK1 Emerges as a Rising Star in Cancer Immunotherapy: An Exclusive Interview with Professor Liao Xuebin of InnoCare Bio

▎Edited by the WuXi AppTec content team

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At the 38th Annual Meeting of the Society for Immunotherapy of Cancer (hereinafter referred to as "SITC 2023") recently held in the United States, MingMed announced the U.S. clinical trial data of its investigational HPK1 small molecule inhibitor PRJ1-3024. The data shows:PRJ1-3024 demonstrated good safety and tolerability and showed encouraging anti-tumor activity in patients with various types of tumors who were resistant to immune checkpoint inhibitors (anti-PD-1 antibody and anti-PD-L1 antibody) treatment.. This data has drawn industry attention to HPK1 as a novel immunotherapy target.

HPK1 (also known as MAP4K1) is fully referred to in Chinese as Hematopoietic Progenitor Kinase 1, a type of protein kinase. It can not only negatively feedback regulate the functions of various immune cells in the anti-tumor immune cycle but also control the expression of PD-1 in T cells. It has been regarded as a potential target in the field of cancer immunotherapy. Within China,Currently, several companies are developing targeted therapies for HPK1. MingMed's PRJ1-3024 is one of the few HPK1 small molecule inhibitors that have entered the clinical stage.

What role does HPK1 play in the tumor immune system? What challenges in current cancer treatment can novel HPK1-based immunotherapies potentially address? What unique advantages does MingMed's PRJ1-3024 offer?With these questions in mind, the WuXi AppTec content team conducted an exclusive interview with Professor Xuebin Liao.Professor Xuebin Liao is currently affiliated with the School of Pharmaceutical Sciences at Tsinghua University and is also the co-founder and scientific advisor of MingMed., he has rich scientific research experience in the field of tumor immunology.

Image Source: Provided by MingMed, Produced by the Content Team of WuXi AppTec

WuXi AppTec Content Team: In your view, what are the key challenges faced by current cancer treatment methods or clinical solutions? And are there any solutions?

Professor Xuebin Liao: The treatment of tumors should focus on early screening and early diagnosis and treatment, which will greatly increase the possibility of a cure. In terms of treatment methods, from traditional radiotherapy and chemotherapy to targeted therapy, and now to immunotherapy, although the methods of tumor treatment are constantly changing, the future trend in clinical solutions will be combination therapy.The ideal state of tumor treatment is to cure cancer or significantly extend the survival time with tumors, so the key challenge lies in preventing tumor recurrence.For example, the current popular antibody-drug conjugates (ADC) and CAR-T products aim to eliminate tumor cells without causing side effects like traditional chemotherapy drugs. After the tumor cells are eliminated, establishing immune memory becomes crucial. If the immune system can return to a normal state while activating immune surveillance, it can effectively prevent tumor recurrence.Eliminating tumor cells and establishing immune memory through two pathways simultaneously should be the future direction.

WuXi AppTec Content Team: Could you share the relationship between HPK1 and diseases? And what challenges in current cancer treatment could immunotherapies based on the HPK1 target potentially address?

Professor Xuebin Liao: At present, tumor immunotherapy mainly relies on the function of T cells to kill tumor cells. HPK1 is a protein kinase, which is mainly expressed in hematopoietic organs and hematopoietic cells.In the signaling pathway, HPK1 is located upstream of PD-1 and is a key kinase expressed in immune cells.。HPK1 Kinase Can Inhibit Immune Function in Various Cells. The research also found that,HPK1 can not only negatively feedback regulate the functions of various immune cells in the anti-tumor immune cycle, but also modulate the expression of PD-1 in T cells.Based on these research findings, HPK1 is considered a promising target in the field of immunotherapy.The development of HPK1 small molecule inhibitors is expected to bring a new treatment option for cancer patients.。

As far as current tumor immunotherapy is concerned, further improving the response rate of tumor immunity is the future research direction.In one category of patients, although immune cells in the tumor microenvironment can infiltrate into the tumor tissue, they are restricted and not in the same space as the tumor cells, resulting in rare encounters between them. For these patients,Therapies targeting HPK1 have the advantage of influencing the tumor microenvironment, enhancing the interaction between immune cells and tumor cells, thereby increasing the immune response rate in this patient population.。

Moreover, from the perspective of mechanism of action, HPK1 small molecule inhibitors are expected to be used in combination with various treatment methods, including chemotherapy, radiotherapy, ADC, CAR-T, and other targeted therapies (especially for

Targeted therapy for KRAS mutations), further improving the treatment outcomes for cancer patients.

WuXi AppTec Content Team: What are the unique features of PRJ1-3024 developed by MingMed? In the clinical studies conducted so far, what therapeutic advantages has PRJ1-3024 demonstrated?

Professor Xuebin Liao：PRJ1-3024 is a small molecule HPK1 inhibitor independently developed by MingMed, designed to treat various advanced solid tumors by enhancing T cell function and anti-tumor immune responses.Currently, MingMed is conducting a Phase 1 clinical trial in the United States, while also carrying out the Phase 1 portion of a Phase 1/2 clinical trial in China to evaluate the safety, tolerability, preliminary efficacy, and pharmacokinetic characteristics of PRJ1-3024.

At the 38th Annual Meeting of the Society for Immunotherapy of Cancer held in the United States this November, we have already announcedPreliminary Data from the PRJ1-3024 Monotherapy Clinical Trial in Tumor Patients Conducted in the United States. The main objective of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for patients. Notably, in the Phase 1 clinical trial of PRJ1-3024,Approximately 87% of the treated population are patients who did not respond to or developed resistance against anti-PD-1 antibody therapy.。

According to the preliminary data of this trial, PRJ1-3024 has the following advantages:: 1) It has a unique kinase spectrum selectivity; 2) Significant efficacy was observed even in patients who did not respond to PD-1 immune checkpoint inhibitors; 3) It exhibits good bioavailability and PK characteristics; 4) The PK-PD relationship is well-defined, with unique advantages in both efficacy and biomarkers; 5) Oral administration, given once daily, offers convenient dosing for patients and high accessibility. Additionally, clinical data also shows,PRJ1-3024 is controllable in terms of immune response and does not overactivate the immune system.。

WuXi AppTec Content Team: What are the key challenges to fully realizing the potential of PRJ1-3024? And what are the potential solutions?

Professor Xuebin Liao：A key challenge is how to identify effective treatment populations and discover new combination therapies.There are many types of tumors and patients, so it is crucial to screen for the population that may benefit from PRJ1-3024 treatment. In the clinical trial design of PRJ1-3024, the team conducted research and evaluations, ultimately selecting patients who had developed resistance after previous treatments with immunotherapies targeting PD-1, PD-L1, CTLA-4, etc., for clinical exploration. This approach allows for a better assessment of whether the HPK1 inhibitor has more advantages compared to prior immunotherapies.

WuXi AppTec Content Team: In the next few years, what milestone developments are expected in MingMed's R&D pipeline?

Professor Xuebin Liao: MingMed's product pipeline is very rich. In addition to the field of tumor immunotherapy, we have made a lot of progress and achievements in areas such as botulinum toxin and ophthalmic drugs.In the next two years, regarding PRJ1-3024, we look forward to achieving results in monotherapy within one or two cancer types, bringing new breakthroughs to the field of cancer immunotherapy. Meanwhile, we will also explore different combination therapy regimens for PRJ1-3024, such as with chemotherapy, ADC, or even CAR-T.Different Treatment MethodsThe therapeutic effect of combination therapy. Moreover, we are highly looking forward to collaborating with various pharmaceutical companies to jointly advance the progress in the field of cancer immunotherapy.

WuXi AppTec Content Team: How do you view the current innovation trends in the biopharmaceutical industry? Where are the innovation opportunities? What are your predictions for the next few years?

Professor Xuebin Liao: The core of innovation is to address unmet clinical treatment needs. Following this starting point,Innovation returns to fundamentals: first, drugs must be safe, and at the same time, they must be effective. Only on this basis can we talk about innovation.。Future innovation opportunities mainly stem from how to enhance patient benefits, which are primarily reflected in two aspects.: First, for patients who previously had no treatment options, there are now new treatment solutions; second, for patients who already had treatment options, there are now new therapies with better safety and comfort, offering patients greater benefits.

WuXi AppTec Content Team: In terms of original innovation, what challenges do you think scientific research translation currently faces? In response to these challenges, which new approaches, methods, or technologies do you believe could potentially break this "curse" and bring more hope to patients?

Professor Xuebin Liao: The challenges facing translational research today are multifaceted. In our research, mice are often used as model animals. Although the experiments are conducted in great detail, different issues often arise when applied clinically.The essence of translational research is to identify biomarkers that can guide medication use or monitor clinical responses after drug administration.。The difficulty lies in whether the drug's response and mechanism align with biomarkers.。Another challenge is——There is a large individual variation in the population, which poses many difficulties for research.. For example, for the same type of tumor, the pathogenic mechanisms can vary at different stages of the disease. Finding the right biomarkers to guide clinical treatment is also a significant challenge.

In the face of these challenges, we still have many solutions. For example, the application of innovative technologies such as big data and artificial intelligence plays a significant role in the processes of drug discovery and biomarker exploration. The emergence and development of new disciplines like machine learning and systems biology will also advance the progress of translational research. Additionally, the use of proteomics, metabolomics, and other omics studies, as well as various sequencing methods including single-cell sequencing, will greatly benefit translational research.

WuXi AppTec Content Team: How do you view the role of collaboration in new drug development? And what kind of collaboration do we need to accelerate the arrival of innovative therapies?

Professor Xuebin LiaoIn the past few years, every startup in drug development wanted to become "Big Pharma." However, the current environment requires startups to face reality and strengthen external collaborations. Startups have the advantage of strong R&D capabilities, being small and fast, while large companies possess comprehensive clinical systems and abundant funding. Therefore, after a product enters the clinical stage, collaboration between startups and large companies to jointly advance clinical development benefits the project by expediting clinical trials, regulatory submissions, and market entry.

WuXi AppTec Content Team: What other personal suggestions do you have for how the industry can collectively improve R&D efficiency, increase the accessibility of innovative therapies, and benefit patients?

Professor Xuebin Liao: I think there are several aspects: first,Make good use of artificial intelligence and big data; Second,Promote the Discovery of More New Technologies; Third,Further promote the progress and development of basic scientific research. Breakthroughs in science and advancements in technology will promote drug development. For example, big data and artificial intelligence will increase the success rate of drug development by identifying specific populations early on, helping us quickly find effective results during the clinical trial process.TreatmentThe population can save clinical resources and reduce R&D costs.

WuXi AppTec Content Team: Looking ahead to the upcoming 2024, can you use a single word or sentence to describe your expectations?

Professor Xuebin Liao:A thousand sails pass by the sunken boat, and ten thousand trees flourish before the sick tree.

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