Stem Cells for Immune System Regeneration to Fight Cancer

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Grant Award Details

Grant Type:

New Faculty II

Grant Number:

RN2-00902

Investigator(s):

Name:

Dr. Antoni Ribas MD/PhD

Institution:

University of California, Los Angeles

Type:

Disease Focus:

Cancer, Melanoma, Solid Tumors

Human Stem Cell Use:

Adult or Tissue Stem Cell

Award Value:

$3,072,000

Status:

Closed

Progress Reports

Reporting Period:

Year 1

The awarded grant supports a patient-oriented research project to genetically engineer the human immune system to become cancer-targeted and provide benefit to patients with metastatic melanoma, a deadly form of skin cancer currently devoid of successful treatment options. During the first funding period we initiated a clinical trial where patients with metastatic melanoma receive immune cells that have been re-directed by gene engineering techniques to become melanoma-specific. The immune cells are obtained from the patient’s own blood and they are manipulated in an in-house clinical grade facility for one week to insert into the cells two genes (T cell receptor or TCR genes) that turn them specific melanoma killer cells, called the. The genetic reprogramming of the immune system cells to express TCR genes is done using a crippled virus called a gene transfer vector. These cells undergo extensive testing to meet the standards of the Food and Drug Administration (FDA) before they can be given back to patients. We give back the TCR re-directed immune cells to patients after receiving a chemotherapy preparative regimen to partially deplete their own immune system so the new cells have the ability to expand. In addition, the patients receive a treatment called high dose interleukin-2 (IL-2) to further allow these cells to expand. Furthermore, these patients receive three doses of dendritic cell vaccines, also generated from the patient’s own blood cells, which further helps the TCR re-directed immune cells to attack the melanoma lesions. Seven patients have been enrolled onto this study at this time. Two patients are too early to evaluate and in the other patients we have early encouraging evidence of antitumor activity. We are conducting studies to determine how these cells behave in the patients by analyzing if they acquire ability to persist long term, what we call T memory stem cells. These are ongoing studies that will continue to the next funding period. Finally, we have initiated the work to set up a follow up clinical trial where we will genetically modify patient’s blood stem cells, which we hypothesize will allow the continuous generation of TCR re-directed immune cells starting from the stem cells. This would provide means for immune system regeneration that would have applications to other cancers and non-cancer diseases like infectious diseases and autoimmune diseases. To this end, a new gene transfer vector has initiated clinical grade production to allow us to use it in the proposed next generation clinical trial.

Reporting Period:

Year 2

The awarded grant supports a patient-oriented research project to genetically engineer the human immune system to become cancer-targeted and provide benefit to patients with metastatic melanoma, a deadly form of skin cancer currently devoid of successful treatment options. During the second funding period we continued to conduct a clinical trial where patients with metastatic melanoma receive immune cells that have been re-directed by gene engineering techniques to become melanoma-specific. The immune cells are obtained from the patient’s own blood and they are manipulated in an in-house clinical grade facility for one week to insert into the cells two genes (T cell receptor or TCR genes) that turn them specific melanoma killer cells, called the. The genetic reprogramming of the immune system cells to express TCR genes is done using a crippled virus called a gene transfer vector. These cells undergo extensive testing to meet the standards of the Food and Drug Administration (FDA) before they can be given back to patients. Ten patients have been enrolled onto this study at this time. In nine of them there has been evidence of tumor shrinkage, demonstrating the strong therapeutic activity of TCR redirected lymphocytes. However, these have been transient beneficial effects. Our ongoing studies point to a loss of function of the TCR transgenic cells over time. Therefore, it is of key importance to develop means to optimize the presence of long lasting memory cells. As proposed in the initial grant we are conducting studies to characterize the presence of T memory stem cells, which are cells able to self-replicate and maintain a cancer-fighting immune system for long periods of time. These are ongoing studies that will continue to the next funding period. In addition, we have put a lot of work to set up a follow up clinical trial where we will genetically modify patient’s blood stem cells, which we hypothesize will allow the continuous generation of TCR re-directed immune cells starting from the stem cells. This would provide means for immune system regeneration that would have applications to other cancers and non-cancer diseases like infectious diseases and autoimmune diseases. To this end, we have generated new gene transfer vectors that are being studied for optimal function in relevant animal models to then allow an informed decision on the vector to take for clinical grade production and use it in the proposed next generation clinical trial.

Reporting Period:

Year 3

The awarded grant supports patient-oriented research with the ultimate goal of reconstituting a cancer-fighting immune system. The research is conducted in samples obtained from patients with metastatic melanoma, a deadly form of skin cancer, and using preclinical models. During the third funding period we have introduced modifications to enhance the ability of immune cell long term persistence within a clinical trial where patients with metastatic melanoma receive immune cells that have been re-directed by gene engineering techniques to become cancer-fighter cells. The immune cells are obtained from the patient’s own blood and they are manipulated in an in-house clinical grade facility for one week to insert into the cells two genes (T cell receptor or TCR genes) that turn them specific melanoma killer cells. The genetic reprogramming of the immune system cells to express TCR genes is done using a crippled virus called a gene transfer vector. These cells undergo extensive testing to meet the standards of the Food and Drug Administration (FDA) before they can be given back to patients. When using a higher number of the TCR genetically engineered lymphocytes that are not frozen before their infusion to patients we are now detecting a higher ability of these cancer-fighting immune system cells to persist for long periods of time. This may be because the protocol modifications were guided to foster a higher ability to generate immune system cells that have long term memory and ability to self-renew (termed T memory stem cells). The detection of these cells is one of the research projects in this grant, since there is no defined set of markers for them. We have been testing several strategies to detect these cells and these are ongoing studies that will continue to the next funding period. In addition, we have continued to move forward to set up a follow up clinical trial where we will genetically modify patient’s blood stem cells, which we hypothesize will allow the continuous generation of TCR re-directed immune cells starting from the stem cells. This would provide means for immune system regeneration that would have applications to other cancers and non-cancer diseases like infectious diseases and autoimmune diseases. To this end, we have tested the performance of two candidate gene transfer vectors for optimal function in humanized animal models. The results of these studies have demonstrated that one of the vectors is better suited for continued testing and it is the one that we plan to take into clinical grade production with the pre-IND activities being completed during the next funding period.

Reporting Period:

Year 4

Reporting Period:

Year 5

Grant Application Details

Application Title:

Stem Cells for Immune System Regeneration to Fight Cancer

Public Abstract:

This proposal will define the biology of stem cell engineering to produce a cancer-fighting immune system. The immune system protects our body against most outside threats. However, it frequently fails to protect us from cancer. The T cell receptor (or TCR), a complex protein on the surface of an immune cell (or lymphocyte), allows to specifically recognize cancer cells. The TCR functions like a steering wheel for lymphocytes, allowing them to travel around the body and specifically find and attack cancercells. The goal of this research is to put TCR genes into stem cells to generate a renewable source of cancer-fighting lymphocytes. The studies in mice provide compelling evidence that inserting TCR genes into stem cells has several advantages for the progeny lymphocytes, allowing them to better fight cancer. The next step is to bring this approach to patients with cancer. The main reason is that the TCR genes inserted into stem cells allow the generation of a larger army of TCR re-directed cancer-fighting killer lymphocytes. I have dedicated most of my prior work to make the transition from studies in mice to the bedside. I have gaind the expertise to conduct clinical trials using cells as targeted drugs from patients. This experience has allowed me to design and start working on the clinical trials that will test the concept of inserting TCR genes into progenitors of lymphocytes and give them to patients. With my collaborators at other institutions, we have raised the adequate resources from private foundations and the NIH to initiate clinical trials inserting TCR genes into lymphocytes. I request additional funds from CIRM to allow me to extract the most information from the clinical trials and then help take them one step further by ultimately testing the use of hematopoietic stem cells (HSC) and induced pluripotent cells (iPS) to engineer a cancer-fighting immune system. There are several challenges tha need to be addressed, including what is the best approach to generate both immediate and long-term cancer fighting cells, what are the optimal stem cells to target, and how they should be manipulated and given to patients in the clinic. The study of samples obtained from patients participating in pilot clinical trials will provide information how to design new clinical trials using the method of inserting the cancer-specific TCR genes into stem cells. The experience of regenerating a cancer-fighting immune system in humans could then be applied to multiple cancer types and to infectious diseases that currently lack good treatment options.

Statement of Benefit to California:

Preclinical studies have validated the concept that the immune system can be harnessed to fight cancer. However, clinical testing has failed short of expectations. I propose to genetically program the immune system starting from stem cells with the hope of advancing cancer immunotherapy. Malignant melanoma will be the cancer for the initial testing of this approach. Melanoma has a track record of being “immune-sensitive” and there are well-defined antigens against which the immune system can be targeted. Melanoma is the cancer with the fastest rising incidence in the U.S. This disease impacts heavily in our society, since it strikes adults at the prime years of life (30-60 years old). In fact, melanoma is the second cancer cause of lost of productive years given its incidence early in life and its high mortality once it becomes metastatic. The problem is particularly worrisome in areas of the world like California, with large populations of persons originally from other latitudes with much lower sun exposure and with skin types unable to handle the increased exposure to ultraviolet (UV) light in California. Although most frequent in young urban Caucasians, melanoma also strikes other ethnicities. The incidence of acral melanoma (non-UV light induced melanoma that develops in the palms and soles) has also steadily increased in Hispanics and Blacks over the past decades. Early melanoma can be cured with surgery. Therefore, programs aimed at early detection have the highest impact in this disease. Once it becomes metastatic, melanoma has no curative standard therapy. Despite this grim outlook, it has been long known that occasional patients participating in experimental immunotherapy protocols have long remissions and are seemingly cured. This proposal aims at incorporating the most current knowledge arising from preclinical research and prior clinical experimentation of immunotherapy strategies to engineer the immune system genetically to better fight metastatic melanoma. Bringing new science from the laboratory to the bedside requires well-designed, well-organized and informative clinical trials. It is not enough to show some responses, we need to understand how they develop and why some patients respond and other do not. Therefore, the analysis of stem cell-based immune system engineering within clinical trials proposed herein requires thorough analysis of patient-derived samples to inform the follow-up clinical testing. Information resulting from the genetic engineering of the immune system in patients with melanoma will help develop studies to direct the immune system to fight other cancers and infectious diseases like HIV. Once optimized, I envision the ability to clone T cell receptor (TCR) genes specific for tumor or infectious disease antigens expressed by different cancers or infectious agents, and use these TCRs to genetically program the patient’s immune system to attack them.

Publications

Future Oncol (2010): Adoptive cell transfer of T-cell receptor-engineered lymphocytes: lessons from recent modeling. (PubMed: 21142653)
Clin Cancer Res (2014): Adoptive transfer of MART-1 T cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. (PubMed: 24634374)
Mol Ther (2013): Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells. (PubMed: 23380815)
Proc Natl Acad Sci U S A (2011): Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. (PubMed: 22123951)
J Transl Med (2009): CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. (PubMed: 19457253)
Clin Cancer Res (2009): Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. (PubMed: 19789309)
Cancer Res (2014): HSV-sr39TK positron emission tomography and suicide gene elimination of human hematopoietic stem cells and their progeny in humanized mice. (PubMed: 25038231)
J Nucl Med (2010): Imaging of CTLA4 blockade-induced cell replication with (18)F-FLT PET in patients with advanced melanoma treated with tremelimumab. (PubMed: 20150263)
J Immunother (2010): The impact of ex vivo clinical grade activation protocols on human T-cell phenotype and function for the generation of genetically modified cells for adoptive cell transfer therapy. (PubMed: 20842061)
Proc Natl Acad Sci U S A (2010): Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. (PubMed: 20624956)
Nature (2010): Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. (PubMed: 21107323)
PLoS One (2010): Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma. (PubMed: 20856802)
Cancer Discov (2013): Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy. (PubMed: 23519018)
Q J Nucl Med Mol Imaging (2010): PET imaging of the immune system: immune monitoring at the whole body level. (PubMed: 20559199)