Stem Cell-Based Targeted Immune Therapy for Cancer

Funding Type: 
Disease Team Research I
Grant Number: 
ICOC Funds Committed: 
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 two Investigational New Drug (IND) applications within the grant period for the genetic modification of hematopoietic (blood) stem cells (HSC) from patients with advanced forms of an aggressive skin cancer (malignant melanoma) to genetically redirect the patient’s immune response to specifically attack the cancer. Evaluation of 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 cancer cells slowly decrease over time 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, providing prolonged protection against the cancer. The 1st IND filing (year 2/quarter 2) will use the modified HSC in end-stage melanoma patients. By the end of year 4, we will expand our efforts to a 2nd IND for a new engineered HSC clinical trial that will increase the specificity of the HSC to other cancers. 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) Our wealth of investigator initiated cell based clinical research and our Human Gene Medicine Program
3) Experience receiving a combined 15 investigator initiated INDs for research with 157 patients in Phase I and II trials
4) Ability to leverage significant institutional resources of on-going HSC laboratory and clinical research and co-support with over $1M 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 the 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 (30-60 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 in large populations with skin types sensitive to the increased exposure of ultraviolet light. Most frequently seen in young urban Caucasians, melanoma also strikes other ethnicities with 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 which contains 2 INDs for the genetic modification of the patient’s own hematopoietic stem cells (HSC) for the immunotherapy of end-stage melanoma allowing sustained production of cancer-reactive blood 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 is that genetically modified stem cells in the patient’s body will continuously generate melanoma-targeted blood cells providing prolonged protection against the cancer. During the grant period we will also develop and produce a GMP quality second IND vector expressing a T cell receptor for NY-ESO, an antigen expressed by 10-30% of all cancers, thereby broadening the applicability of this approach. The therapeutic principles and procedures developed here will be applicable to a wide range of cancers. GMP reagents and clinical protocols developed by our team will be transferrable to other centers where bone marrow and peripheral blood stem cell transplantation procedures are done.

Our institution, with its college and multiple professional schools, receives over $900M in extramural research support with a major economic impact throughout the region. The proposal will build upon a strong foundation of basic and clinical research and further solidify on-going institutional collaborations that will further link the activities of four premier research institutions.