Stem Cells for Immune System Regeneration to Fight Cancer

Stem Cells for Immune System Regeneration to Fight Cancer

Funding Type: 
New Faculty II
Grant Number: 
RN2-00902
Award Value: 
$3,072,000
Disease Focus: 
Melanoma
Cancer
Status: 
Closed
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

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.

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.

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.

Year 4

This grant proposed the conduct of pre-clinical work to support the use of stem cells to regenerate a cancer-fighting immune system in mice and humans, and bedside-to-bench work to analyze populations of cells with potential ability to function as long term repopulating T lymphocytes obtained from patients treated within a phase 1 clinical trial. During this past year we have made progress to continue our study the biology of T cells with characteristics of long term memory immune cells, termed T memory stem cells (TMSC). We have recently studied the ability to use specific small molecule targeted inhibitors to increase the fraction of mature T cells with TMSC characgteristics, which will improve our ability to characterize them. We have also advanced our studies to test the transplantation of hematopoietic stem cells (HSC) genetically engineered to express T cell receptors (TCR) and provide a continuous progeny of TCR transgenic mature T cells in humanized mouse models. This work provides the rationale to allow us advancing our plans to conduct a clinical trial based on the transplantation of HSC genetically engineered to express TCR to regenerate a cancer-fighting immune system. We have successfully competed for a CIRM disease team award and have gone through a pre-IND meeting with the FDA to adequately plan for such a clinical trial to be started in approximately two years.

Year 5

We have continued to make progress to reach the proposed goals of this grant: We have further characterized immune cells that naturally express three transcription factors that transform normal cells into pluripotent stem cells. We are interested in determining if these immune cells with pluripotency transcription factors are long term memory cells able to maintain immune responses. In parallel, we have continued to advance our studies to bring a new approach to the clinic based on the genetic modification of blood stem cells to regenerate a cancer-fighting immune system. In the past year we have discussed our plans with the Food and Drug Administration and we have proceeded to follow their recommendations on what needs to be provided to open such a clinical trial. This clinical trial will be further developed within a newly approved CIRM disease team grant.

Publications

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