HER2-Targeting Chimeric Antigen Receptor Myeloid Cells Derived from Expanded Cord Blood Hematopoietic Stem and Progenitor Cells for Ovarian Cancer Immunotherapy
Abstract
Rationale: Cellular immunotherapies have revolutionized the field of cancer therapy by harnessing the immune system to target malignant cells. However, current approaches have many limitations that are restricting the field; both in terms of cost and efficacy against solid tumors. To address the issues of cost, the field has sought to overcome the constraint of using the patient’s own immune cells by pursuing alternative cellular sources to make the process scalable, commercially viable, and consequently accessible to more patients. The hematopoietic stem and progenitor cells (HSPCs) in umbilical cord blood would appear to be an ideal source for immunotherapies, but are conspicuously absent from the field’s choices. This rarity is likely in part because cord blood units (CBUs) in cord blood banks are expensive ($30,000 - $50,000 each) and relatively scarce. Thus, to use cord blood HSPCs as a source for immunotherapies, a process must either produce thousands of doses per banked cord or use cords with cell numbers below the bankable threshold of cells. At present, there are no existing published methods for expanding progenitor immune cells (from which all different types of immune cells are derived) to the scale we are proposing and as such, most cellular therapies are developed from mature cells, which comes with a number of well-known difficulties. In addition to this, the vast majority of cellular immunotherapies in development focus on modifying lymphoid cells. These are a certain type of immune cells that participate in fighting cancer cells. However, these therapies, while powerful, neglect a two-pronged ally in the anticancer effort: myeloid cells (another type of cancer- fighting immune cells) and relatedly, the myeloid cells’ ability to activate the patient’s own lymphoid cells. Objective: This work will pursue the objective of expanding immune progenitor cells from cord blood, thus deriving a large number of myeloid cells. The objective is to turn those cells into cancer fighting cells by both creating conditions priming them to fight cancer as well as genetically modifying them so that they directly recognize and target the cancer cells. If successful, we will show that these cells are superior to the combination of unmodified cells combined with a cancer-targeting antibody in a 3D spheroid tumor model that recreates the challenging conditions immune cells face when confronted with solid tumors in cancers such as ovarian cancer. Aims: To test the function of cancer-targeting myeloid cells, we first need to validate that we can derive cells with the correct anti-cancer attributes from expanded, cord blood-derived HSPCs, and importantly, that this process efficiently derives large numbers of modified cells from the starting pool (Aim 1). We will then test how well these cells function in killing of ovarian cancer cells in several types of ovarian cancer models and compare to the function of unmodified cells combined with anti-cancer antibodies (Aim 2). Overarching Challenge: The vast majority of cellular immunotherapies in development focus on modifying lymphoid cells to target and kill cancer, partially due to practical considerations we intend to overcome. Within this project, we will establish expanded HSPC (xHSPC)-derived myeloid cells as a new tool in the fight against solid tumors, that can complement or replace existing treatments. Translatability: This project is highly translatable by nature with very clear potential clinical application and clinical testing pathway. Our innovation targets employing expanded cord blood HSPCs to overcome many limitations as a viable cell source for immunotherapies, while focusing on a myeloid cell approach together with chimeric antigen receptors targeting cancer. This presents a very promising and yet untested treatment paradigm with significant potential impact for ovarian cancer patients and additional cancer patients. Translatio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211014
Entities
People
- Jesse Cotari
Organizations
- United States Army