Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Hormones

Hormone Antagonists

One time infusion Modified T-Cells given through a vein in the arm or a catheter over a 30-60 minute period.

Gene Modified T Cells

Richard P Junghans, PhD, MD

This study tests the safety and tolerability of autologous anti-PSMA gene-modified T cells (designer T cells) in hormone refractory prostate cancer.

The study creates autologous gene-modified T cells against prostate specific membrane antigen (PSMA, unrelated to PSA) (designer T cells) by ex vivo modification of patient T cells. T cells are collected by leukopheresis, transported to the RWMC cGMP Cell Manipulation Core and transduced with retrovirus containing a chimeric antigen receptor (CAR) that is expressed on the modified cells. This CAR links specificity of an antibody against PSMA with signaling domains of the T cell and redirects the recognition of the T cells to engage and kill prostate cancer cells anywhere in the body. These are administered at a dose of 10\^10 with randomization to either low or moderate Interleukin 2 given by CI (continuous infusion) for one month following the T cell infusion. Subsequent subjects will receive 10\^11 cells with Interleukin 2 at either low or moderate dose, in a non randomized manner, depending upon the outcome of the prior cohort. Prior to T cell infusion, all subjects will receive non-myeloablative (NMA) conditioning. This conditioning creates a "space" in the blood and marrow for engraftment of the infused cells to maintain of high level of anti-tumor effector T cells in the body. Each patient is treated with a single dose of T cells, without repeat dosing. Patients are followed for toxicity and response and pharmacokinetics-pharmacodynamics of the infused T cells. Patients are on-study for one-month after their T cell dose.

Trial of Anti-PSMA Designer T Cells in Advanced Prostate Cancer After Non-Myeloablative Conditioning

Phase Ia/Ib Trial of Anti-PSMA Designer T Cells in Advanced Prostate Cancer After Non-Myeloablative Conditioning

Roger Williams Medical Center

Digestive System Diseases

Carcinoma

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

The purpose of this study is to collect data on the safety and effectiveness of 2nd generation designer T cells in patients with colorectal cancer. Designer T cells are prepared by collecting white blood cells from the participant, and then modifying these cells in the laboratory so that they recognize the tumor antigen (CEA). These modified cells are then given back into the participant so that they can attack and kill tumor cells.

T cells can penetrate virtually every biologic space and have the power to dispose of normal or malignant cells as seen in viral and autoimmune diseases and in the rare spontaneous remissions of cancer. However, T cells are easily tolerized to self or tumor antigens and "immune surveillance" has manifestly failed in every cancer that is clinically apparent. It is the goal of this study to supply the specificities and affinities to patient T cells without regard for their "endogenous" T cell receptor repertoire, directed by antibody-defined recognition to kill malignant cells based on their expression of antigen. We will achieve this by preparing chimeric IgCD28TCR genes in mammalian expression vectors to yield "designer T cells" from normal patient cells. Prior studies in model systems demonstrated that recombinant IgCD28TCR could direct modified T cells to respond to antigen targets with IL2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response.

It therefore becomes of paramount interest to extend these studies to a human system of widespread clinical relevance to explore the clinical potential of this new technology. The target antigen for these studies is carcinoembryonic antigen (CEA), which is prominently expressed on tumors of the stomach, colon and rectum, breast, pancreas and other sites. Patients receive a single dose of gene-modified autologous T cells on this dose-escalation trial. Doses are 10\^9, 10\^10 and 10\^11 modified T cells. Patients are monitored for safety and response. Patients are on-study for one month after dosing.

Trial of Second Generation Designer T Cells in Colorectal Carcinoma

Phase II/Pilot Trial of Second Generation Designer T Cells in Colorectal Cancer

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Neoplasm Metastasis

Stomach Neoplasms

Lung Neoplasms

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplastic Processes

Stomach Cancer

Immunomodulating Agents

All participants will receive gene modified T cells, with concomitant IL2 for 30 days post infusion.

Subjects will undergo T cell leukopheresis. The collected T cells will be genetically modified, and then re-infused peripherally. IL2 will be given concomitantly for 30 days post modified T cell infusion via CADD pump.

T cells can penetrate virtually every biologic space and have the power to dispose of normal or malignant cells as seen in viral and autoimmune diseases and in the rare spontaneous remis-sions of cancer. However, T cells are easily tolerized to self or tumor antigens and "immune surveillance" has manifestly failed in every cancer that is clinically apparent. It is the goal of these studies to supply the specificities and affinities to patient T cells without regard for their "endogenous" T cell receptor repertoire, directed by antibody-defined recognition to kill malignant cells based on their expression of antigen. We will achieve this by preparing chimeric IgCD28TCR genes in mammalian expression vectors to yield "designer T cells" from normal patient cells. This extends the approach of Anderson, Rosenberg and co-workers to introduce or augment expression of genes in patients' T cells in a therapeutic setting.

Prior studies in model systems demonstrated that recombinant IgCD28TCR could direct modified T cells to respond to antigen targets with IL2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response. It therefore becomes of paramount interest to extend these studies to a human system of widespread clinical relevance to explore the clinical potential of this new technology. The target antigen for these studies is carcinoembryonic antigen (CEA) which is predominantly expressed on tumors of the colon and rectum, breast, pancreas and other sites.

CEA is perhaps the most prominent tumor marker among malignancies of epithelial origin: colorectal carcinoma, with 60-94% of tumors positive in patients with advanced disease; breast carcinoma, with 30-60% of metastatic cases positive for CEA; and cancers of the lung, liver, pancreas, head and neck, bladder, cervix and prostate with 30% or more with CEA+ tumors.

The application of these therapies in the four Phase II/Pilot clinical sub studies listed below proceed after collecting patient lymphocytes by leukapheresis, which are then modified by transfer of the chimeric gene for Ig-CD28-TCRzeta. Cells are selected in culture with amplification and activation of the now-specific anti-tumor T cells. These are then re infused into the patients, with IL2 supplementation, and toxicity and response are monitored.

There are four sub studies embedded within this Phase II Study of Second Generation Designer T Cells in CEA-expressing Adenocarcinomas. The embedded studies are:

* A Phase II Pilot Study of Second Generation Anti CEA Designer T Cells in Gastric Cancers (CEA-G)
* A Phase II Pilot Study of Second Generation Anti CEA Designer T Cells in Colorectal Cancers (CEA-C)
* A Phase II Pilot Study of Second Generation Anti CEA Designer T Cells in Lung Cancers (CEA-L)
* A Phase II Pilot Study of Second Generation Anti CEA Designer T Cells in Solid Tumors (CEA-S)

A total of 12 subjects per protocol or a total of 48 subjects will be enrolled combining the enrollment of the 4 CEA-expressing protocols.

Phase II/Pilot Study of 2nd Generation Anti-CEA Designer T Cells in Adenocarcinomas

"Phase II/Pilot Study of 2nd Generation Anti-CEA Esigner T Cells in Adenocarcinomas"

Monitoring of CEA levels, pre and post infusion of T cells. Monitoring of CT and PET scans pre and post infusion.

Monitoring and recording of all adverse and serious adverse events using CTC 4.0 criteria.

Principal Investigator

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

Analgesics

Interleukin-2

Analgesics, Non-Narcotic

Gene Modified T Cells Phase Ia: One time infusion Modified TCells given through a vein in the arm or a catheter over a 30-60 minute period

One time infusion Modified T Cells without or with (randomized) continuous infusion outpatient interleukin 2 (IL2) for two weeks

Gene Modified T Cells and Interleukin 2

The purpose of this study is to collect data on the safety and effectiveness of 2nd generation designer T cells in patients with breast cancer. Designer T cells are prepared by collecting white blood cells from the participant, and then modifying these cells in the laboratory so that they recognize the tumor antigen (CEA). These modified cells are then given back to the participant so that they can attack and kill tumor cells.

T cells can penetrate virtually every biologic space and have the power to dispose of normal or malignant cells as seen in viral and autoimmune diseases and in the rare spontaneous remissions of cancer. However, T cells are easily tolerized to self or tumor antigens and "immune surveillance" has manifestly failed in every cancer that is clinically apparent. It is the goal of this study to supply the specificities and affinities to patient T cells without regard for their "endogenous" T cell receptor repertoire, directed by antibody-defined recognition to kill malignant cells based on their expression of antigen. We will achieve this by preparing chimeric IgCD28TCR genes in mammalian expression vectors to yield "designer T cells" from normal patient cells. Prior studies in model systems demonstrated that recombinant IgCD28TCR could direct modified T cells to respond to antigen targets with IL2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response.

It therefore becomes of paramount interest to extend these studies to a human system of widespread clinical relevance to explore the clinical potential of this new technology. The target antigen for these studies is carcinoembryonic antigen (CEA), which is prominently expressed on tumors of the stomach, colon and rectum, breast, pancreas and other sites.

For the Phase Ia component, patients receive a single dose of gene-modified autologous T cells on this dose-escalation trial. Doses are 10\^9 and 10\^10 modified T cells. Patients are monitored for safety and response. Patients are on-study for one month after dosing.

For the Phase Ib component, patients receive a fixed dose of gene-modified T cells (10\^11 cells), randomized to receive T cell growth factor interleukin 2 (+IL2) \[Experimental\] or not (-IL2) \[Control\]. The IL2 is administered outpatient by continuous infusion for a two-week period. On Day +2 and Day +10, the patient's tumor is biopsied to assess the designer T cell presence in the tumor as a means of judging the benefit of added IL2. Patients will also be followed for tumor response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial of Anti-PSMA Designer T Cells in Advanced Prostate Cancer After Non-Myeloablative Conditioning	NCT00664196	Prostate Cancer	Gene Modified T...	18 Years -	Roger Williams Medical Center
Trial of Second Generation Designer T Cells in Colorectal Carcinoma	NCT00673322	Colorectal Canc...	Gene Modified T...	18 Years -	Roger Williams Medical Center
Phase II/Pilot Study of 2nd Generation Anti-CEA Designer T Cells in Adenocarcinomas	NCT01723306	Metastatic Canc...	Gene Modified T...	18 Years - 80 Years	Roger Williams Medical Center
Trial of Anti-PSMA Designer T Cells in Advanced Prostate Cancer After Non-Myeloablative Conditioning	NCT00664196	Prostate Cancer	Gene Modified T...	18 Years -	Roger Williams Medical Center
Trial of 2nd Generation Anti-CEA Designer T Cells in Metastatic Breast Cancer	NCT00673829	Breast Cancer	Gene Modified T... Gene Modified T...	18 Years -	Roger Williams Medical Center
Trial of Second Generation Designer T Cells in Colorectal Carcinoma	NCT00673322	Colorectal Canc...	Gene Modified T...	18 Years -	Roger Williams Medical Center
Trial of 2nd Generation Anti-CEA Designer T Cells in Metastatic Breast Cancer	NCT00673829	Breast Cancer	Gene Modified T... Gene Modified T...	18 Years -	Roger Williams Medical Center
Phase II/Pilot Study of 2nd Generation Anti-CEA Designer T Cells in Adenocarcinomas	NCT01723306	Metastatic Canc...	Gene Modified T...	18 Years - 80 Years	Roger Williams Medical Center
Trial of Second Generation Designer T Cells in Colorectal Carcinoma	NCT00673322	Colorectal Canc...	Gene Modified T...	18 Years -	Roger Williams Medical Center

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