Focusing on the Tumor Microenvironment Leads to Novel Drug Targets

Pyxis Oncology is using new insights about the genetics of immune cells in the tumor microenvironment to develop a pipeline of new antibodies that enhance the immune response, even in tumor types historically unresponsive to cancer immunotherapies.

Why the Tumor Microenvironment is Important

While many patients with cancer exhibit immune responses to tumors, the T cells involved in that response often do not function properly in the tumor microenvironment. Most patients do not even have these “hot” tumors; they have what are known as “cold” tumors, or non-T cell–inflamed tumors with hostile microenvironments that prevent immune cells from entering their cores and eliminating the tumor. These “cold” tumors require novel therapeutic approaches to interrupt the negative regulation driven by tumor cells and to promote increased immune cell infiltration and motility. 

Current medicines, including leading immunotherapies such as PD-1 and PD-L1 inhibitors, do target T cells located within the tumor microenvironment. However, despite success to date, many patients still do not respond clinically. By focusing more deeply on the properties of immune cells within the tumor microenvironment, a better understanding of the mechanisms involved in their deactivation/inactivation is being achieved, and additional novel therapeutic targets are being identified for restoring or initiating endogenous immune cell function. As several of these targets appear only to be expressed by T cells within tumors, it is possible that drugs specifically targeting these molecules will have fewer off-target effects.

Transitioning from the University Lab

The initial research exploring the tumor environment was conducted in the Gajewski laboratory  at the University of Chicago. By focusing on the unique biology of T cells within tumors, the team discovered immunoregulatory targets tied directly to the biology of the tumor microenvironment. Analysis of tumor antigen–specific tumor-infiltrating lymphocytes (TILs) within hot tumors, and of tumor cell signaling pathways within cold tumors, led to the identification of new genes representing hundreds of molecules not previously identified in the literature as having importance in T cell function or anti-tumor immunity.

Molecules studied to date can act as positive or negative regulators of T cell infiltration and function. These molecules were only observed on dysfunctional T cells in the tumor microenvironment but were not detected when properly functioning T cells led to tumor shrinkage. These are being pursued by Pyxis as targets for novel antibody-based immunotherapies.

Genetic mouse models have already been developed for the top candidates. When tumors were implanted in these models, strong changes in tumor growth were observed, indicating that these are mission-critical molecules for regulating cancer growth. These genetic and interventional preclinical proof-of-concept studies suggest the potential for new effective foundational monotherapies, or drugs that can be used in combination with other cancer therapies.

The Longwood Fund, a Boston-based life sciences venture capital firm that focuses on founding, managing and building healthcare companies, drove the launch of Pyxis Oncology with the assistance of the University’s Polsky Center for Entrepreneurship and Innovation. In July 2019, Pyxis Oncology announced its $22 million Series A financing with the support of Leaps by Bayer, Longwood, Agent Capital and Ipsen.

Forming Pyxis Oncology enables the evaluation of multiple candidates simultaneously with the goal of speeding up their translation from the lab to first-in-human studies. Initially focusing on antibodies and fusion proteins allows for the use of a well-established path to development and commercialization

Head Start

With access to the research already underway, Pyxis is hitting the ground running and is well-positioned to ramp up the scale of production of antibodies for its priority candidates based on the work already completed. Pyxis is also developing the next tier of targets for additional candidates

Maintaining Close Relationship

Pyxis will continue to maintain a close relationship with the Gajewski laboratory at the University of Chicago through a Sponsored Research Agreement (SRA). The company will focus on development and commercialization of new therapies, while the academic laboratory will continue to explore in greater detail the deeper biology and mechanisms underlying the control of immune cells in the tumor microenvironment. As additional insights are gained, they will benefit Pyxis in terms of improving how new drugs are developed and what biomarkers will be used for patient selection. In essence, the relationship will serve as a catalyst for accelerating and de-risking the entire development and commercialization process.

Shaan C. Gandhi, M.D., Ph.D.

Shaan is President of Pyxis and serves as a Principal at Longwood Fund. Previously, Shaan was Chief Medical Officer of Wellable, a mobile corporate wellness startup, as well as a consultant with the TriZetto Corporation, a healthcare analytics and claims processing firm. He holds an M.D. from Harvard Medical School, an MBA from Harvard Business School, a D.Phil. in medical oncology from the University of Oxford, and a B.S. in biochemistry from Case Western Reserve University.