Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Lung Neoplasms

Melanoma

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 an CD103 and expanded in vitro. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.

Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 and CD103 and expanded in vitro in the presence of PH-762, a silencing RNA that reduces the expression of the checkpoint inhibitor PD-1. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.

intravenous infusion of T cell suspension

DP CD8 TIL

DP CD8 TIL KD

Low dose IL-2 delivered subcutaneously for 1, 2 or 3 weeks

Low dose IL-2

Colin J Thalhofer, PhD

Ryan D Montler, MBA

Christopher B Fountain, RN, BSN, OCN

Brendan D Curti, MD

The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.

Our research identified a subpopulation of CD8 tumor infiltrating lymphocytes (TIL) highly enriched for tumor reactivity that can be identified and isolated based on the co-expression of CD39 and CD103. The investigators refer to this tumor-reactive cell population as DP CD8 TIL. The DP CD8 TIL can constitute as few as 2% and up to 70-80% of the CD8 TIL directly isolated from tumors, suggesting that in any given patient a substantial percentage of their CD8 TIL can be bystanders lacking tumor specificity. The CD8 DP TIL were highly enriched for cells that recognize autologous tumor as evidenced by interferon gamma production, 4-1BB upregulation and autologous tumor cell killing. The investigators also found that T cell receptors within the CD8 DP TIL population share very little overlap with the other sub-populations of CD8 TIL, suggesting that they have a distinct antigen recognition pattern.

The DP CD8 TIL express high levels of PD-1 especially when encountering tumor Ag(s) in situ. Pre-clinical experiments have shown that the potency of DP CD8 TIL can be enhanced by decreasing PD-1 checkpoint expression by incubating them with siRNA that targets PD-1. The investigators hypothesize that transient knockdown of PD-1 expression will enable DP CD8 TIL to initiate a more effective and persistent anti-tumor response without increasing toxicity. The investigators refer to DP CD8 TIL after PD-1 knockdown as DP CD8 TIL KD. Although preclinical experiments have shown the value of siRNA modulation of PD-1 in DP T cells, this strategy has not been studied in humans. The main goals of this phase I first-in-human study are to define toxicity and understand the biology and anti-tumor activity of DP CD8 TIL alone and with siRNA PD-1 modulation. Thus, the trial is designed as a randomized comparison of DP CD8 TIL and DP CD8 TIL KD with comprehensive immune monitoring as detailed below.

Lymphodepleting chemotherapy just before adoptive transfer facilitates proliferation and persistence of adoptively transferred T cells as has been demonstrated in other adoptive cellular therapy trials over the last 30 years. Similarly, interleukin-2 (IL-2) administered after adoptive transfer enhances T-cell proliferation, persistence, and cytotoxicity. The investigators have also performed pre-clinical experiments confirming the need for IL-2 after DP CD8 TIL adoptive transfer to achieve maximum antitumor effect in a human xenograft model. Cyclophosphamide and fludarabine will be given prior to adoptive transfer of the DP CD8 TIL and high dose IL-2 (600,000 IU/kg IV with a maximum of 6 doses over 6 days) will be administered starting within 24 hours of the adoptive transfer followed by subcutaneous IL-2 in dose-escalation cohorts of IL-2, 5 MIU/m2 TIW starting on day +8 for 1 weeks, 2 weeks or 3 weeks if tolerated.

Autologous adoptive T cell therapy provided to three cohorts of patients receiving supportive subcutaneous IL-2 therapy for one, two ,or three weeks. Each cohort will be randomized between therapy with DP CD8 TIL or DP CD8 TIL having PD-1 expression reduced by silencing RNA during invitro cell expansion

Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors

Phase I Randomized Open Label Trial Investigating Adoptive Transfer of CD39+CD103+CD8+ Tumor-isolated T Cells (AGX148) Alone or Combined With siRNA Modulation of PD-1 (AGX148/PH-762) in Patients With Advanced Solid Tumors

Frequency and severity of treatment-related adverse events as assessed by CTCAE v5.0 in participants treated with DP CD8 TIL adoptive cell therapy with and without ex vivo siRNA PD-1 modulation after lymphodepleting chemotherapy and followed by high-dose and low-dose IL-2.

Objective response using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria in participants treated with DP CD8 TIL adoptive cell therapy with and without ex vivo siRNA PD-1 modulation after lymphodepleting chemotherapy and followed by high-dose and low-dose IL-2.

Adoptively transferred T cells circulating in the peripheral blood will be identified and quantified over time to identify any differences in the persistence of DP CD8 TIL and DP CD8 TIL KD.

within each cohort of participants receiving 1, 2 or 3 weeks of low-dose subcutaneous IL-2 administration

between different cohorts of low-dose subcutaneous IL-2 administration

Phio Pharmaceuticals Inc.

Providence St Joseph Health

AgonOx, Inc.

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

All Drugs and Chemicals

Mitogens

The ACT will be administered as two intravenous (i.v.) injections of GMP TCR T cells per week for 6 weeks.

Escalating dose per week, from 1 x108 cells (week 1) to 2x109 cells (week 4 onwards) using a central venous catheter. The doses listed indicate the maximum number of T cells per injection at any given time point.

T cell receptor based therapy of metastatic colorectal cancer with mRNA-engineered T cells targeting mutant transforming growth factor beta receptor type II (TGFβII)

Adoptive Cell Therapy (ACT)

Svein Dueland, MD PhD

T Cell Receptor Based Therapy of Metastatic Colorectal Cancer With mRNA-engineered T Cells Targeting Transforming Growth Factor Beta Receptor Type II (TGFβII)

Patients with advanced metastatic colorectal cancer who have no other effective treatment options will be offered the treatment. These patients have a poor prognosis, and there is a strong need for improved therapy.

The patients will be given adoptive cell therapy (ACT) with Radium-1 TCR+ T cells transiently redirected against the TGFβRII frameshift antigen which is expressed in MSI+ colon cancer. The first report on TCR therapy in colon cancer was targeting carcinoembryonic antigen (CEA) where some evidence of clinical response was seen, but the T-cell function may have been inhibited due to the necessity to resolve the severe colitis which occurred due to the presence of CEA in normal cells in the colon. This demonstrates the feasibility of T-cell therapy in metastatic colon cancer, but also the limitations of targeting CEA as an antigen.

T Cell Receptor Based Therapy of Metastatic Colorectal Cancer

Protocol for Treatment Under Hospital Exemption: T Cell Receptor Based Therapy of Metastatic Colorectal Cancer With mRNA-engineered T Cells Targeting Transforming Growth Factor Beta Receptor Type II (TGFβII)

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0

PFS defined as time from treatment to objective progression (as assessed by RECIST v1.1)

ORR defined as the proportion of patients with an objective tumor response

OS defined as time from treatment to date of death from any cause

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors	NCT05902520	HNSCC Melanoma Gynecologic Can... Colorectal Canc... Lung Cancer Urogenital Canc...	DP CD8 TIL DP CD8 TIL KD Low dose IL-2	18 Years -	AgonOx, Inc.
Adoptive Cell Therapy Using Cancer Specific CD8+ Tumor Infiltrating Lymphocytes in Adult Patients With Solid Tumors	NCT05902520	HNSCC Melanoma Gynecologic Can... Colorectal Canc... Lung Cancer Urogenital Canc...	DP CD8 TIL DP CD8 TIL KD Low dose IL-2	18 Years -	AgonOx, Inc.
T Cell Receptor Based Therapy of Metastatic Colorectal Cancer	NCT03431311	Colorectal Canc...	Adoptive Cell T...	18 Years -	Oslo University Hospital

Spots Global Cancer Trial Database for adoptive cell therapy (act)