Genetic Re-programming of Stem Cells to Fight Cancer

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Award Value: 
Disease Focus: 
Collaborative Funder: 
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Science has made great progress in the treatment of certain cancers with targeted and combination therapies, yet prolonged remissions or cures are rare because most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer.

The study investigators propose to develop an Investigational New Drug (IND) and fully enroll a phase I clinical trial within the grant period to genetically redirect the patient’s immune response to specifically attack the cancer starting from hematopoietic (blood) stem cells (HSC) in patients with advanced forms of the aggressive skin cancer malignant melanoma. Evaluation of immune system reconstitution, effectiveness and immune response during treatment will use imaging with Positron Emission Tomography (PET) scans.

The HSC treatment approach has been validated in extensive studies in the laboratory. The investigators of this grant have recently initiated a clinical trial where adult immune cells obtained from blood are genetically modified to become specific killer cells for melanoma. These cells are administered back to patients. The early data from this study is encouraging in terms of the ability to generate these cells, safely administer them to patients leading to beneficial early clinical effects. However, the adult immune cells genetically redirected to attack cancer slowly decrease over time and lose their killer activity, mainly because they do not have the ability to self-renew.

The advantage of the proposed HSC method over adult blood cells is that the genetically modified HSC will continuously generate melanoma-targeted immune killer cells, hopefully providing prolonged protection against the cancer. The IND filing with the FDA will use the modified HSC in advanced stage melanoma patients. By the end of year 4, we will have fully accrued this phase 1 clinical trial and assessed the value of genetic modification of HSCs to provide a stable reconstitution of a cancer-fighting immune system. The therapeutic principles and procedures we develop will be applicable to a wide range of cancers and transferrable to other centers that perform bone marrow and HSC transplants.

The aggressive milestone-driven IND timeline is based on our:
1) Research that led to the selection and development of a blood cell gene for clinical use in collaboration with the leading experts in the field,
2) Wealth of investigator-initiated cell-based clinical research and the Human Gene Medicine Program (largest in the world with 5% of all patients worldwide),
3) Experience filing a combined 15 investigator initiated INDs for research with 157 patients enrolled in phase I and II trials, and
4) Ability to have leveraged significant institutional resources of on-going HSC laboratory and clinical research contributed ~$2M of non-CIRM funds to pursue the proposed research goals, including the resulting clinical trial.

Statement of Benefit to California: 

Cancer is the leading cause of death in the US and melanoma incidence is increasing fastest (~69K new cases/year). Treatment of metastatic melanoma is an unmet local and national medical need (~9K deaths/year) striking adults in their prime (20-60 years old). Melanoma is the second greatest cancer cause of lost productive years given its incidence early in life and its high mortality once it metastasizes. The problem is severe in California, with large populations with skin types sensitive to the increased exposure to ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities, i.e., steady increases of acral melanoma in Latinos and African-Americans over the past decades.

Although great progress has been made in the treatment of certain leukemias and lymphomas with targeted and combination therapies, few options exist for the definitive treatment of late stage solid tumors. When cancers like lung, breast, prostate, pancreas, and melanoma metastasize beyond surgical boundaries, prolonged remissions or cures are rare and most cancer therapies only inhibit cell growth and/or reduce such growth but do not stop the cancer.

Our proposal, the filing of an IND and the conduct of a phase 1 clinical trial using genetically modified autologous hematopoietic stem cells (HSC) for the immunotherapy of advanced stage melanoma allowing sustained production of cancer-reactive immune cells, has the potential to address a significant and serious unmet clinical need for the treatment of melanoma and other cancers, increase patient survival and productivity, and decrease cancer-related health care costs.

The advantage of the proposed HSC methodology over our current work with peripheral blood cells is that genetically modified stem cells will continuously generate melanoma-targeted immune cells in the patient’s body providing prolonged protection against the cancer. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. Good Manufacturing Practices (GMP) reagents and clinical protocols developed by our team will be transferable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.

Progress Report: 

A strategy in the treatment of cancer by harnessing the immune system, called adoptive cell therapy, is to use an individual’s own immune cells (T cells) and genetically modify them to target them to kill the cancer. Our emerging clinical data demonstrates that these gene-modified T cells are very active in killing tumor cells initially, but they lose their ability to function within a few weeks. This experience points to the need to have a continuous source of gene-modified cells to maintain the ability to kill cancer cells. In this study, we hypothesize that gene-modified stem cells will allow a sustained production of active T cells with antitumor activity. Since there is a delay in the appearance of the T cells that come from stem cells to get out of the bone marrow and into the blood, we will give patients both gene-modified T cells for a first wave of antitumor activity and gene-modified stem cells which will provide a bridge until the stem cells have produced more T cells. The purpose of the current study is to give gene-modified T cells in combination with gene-modified stem cells to reprogram the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein with sustained killing activity. The patient’s own white blood cells and stem cells from their blood are modified in the laboratory using genetic techniques to express a specific receptor against cancer cells. Gene modification of cells involves the transfer of foreign genetic material (DNA) into a cell, in this case the immune system cells and stem cells. This process will endow the recipient immune cells and descendants of the stem cells with the ability to eliminate cancer cells that express the cancer specific protein, NY-ESO-1. The specific receptor against cancer cells that will be transferred to the immune cells and stem cells is called NY-ESO-1 T cell receptor (or TCR). In this study, the gene-modified immune cells will be given in combination with the gene-modified stem cells.

To date, we have manufactured a batch of the lentiviral vector necessary to transfer the NY-ESO-1 TCR into stem cells and have demonstrated that this vector can gene-modify human stem cells. Preclinical safety studies are currently ongoing. We have demonstrated that when mouse stem cells are gene-modified with this lentiviral vector, the stem cells take up residence in the bone marrow and produce appropriate blood cells. There is no detrimental effect on the blood cells that are derived from the stem cells. In vitro assays have also been performed to assess whether the lentiviral vector could potentially transform cells. These studies are ongoing but interim data suggests that there the lentiviral vector has no transforming potential. A preclinical study is also ongoing in mice to assess the safety of combining the gene-modified T cells and stem cells in mice. In addition, a preclinical study was performed to demonstrate that the stem cells are able to be specifically eliminated using ganciclovir, which provides a safety feature in case there was a problem when translating this research to humans. The vector includes a suicide gene which we have shown can be used to kill cells if necessary.

Preparations are ongoing towards opening a clinical trial. The manufacturing process is being optimized, and clinical documents have been submitted to internal committees for review.