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This is a single-arm, phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A\*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT).

This is a single-arm, phase 1 trial of HERV-E TCR transduced CD8+/CD34+ T cells in HLA-A\*11:01 positive patients with metastatic ccRCC. The study is planned based on a Phase 1 3+3 dose escalation design. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a dose limiting toxicity (DLT). Patients with evaluable advanced/metastatic ccRCC will be recruited in up to 4 dose levels.

cell infusion

Richard W Childs, M.D.

Background:

Gene transfer is a new cancer therapy takes white blood cells from a person and grows them in a lab. The cells are changed with a virus to attack tumor cells, then returned to the person. Researchers want to see if this therapy fights kidney cancer cells.

Objective:

To see if gene transfer is safe and causes tumors to shrink.

Eligibility:

People at least 18 years old with certain kidney cancer

Design:

Participants will be screened with blood and urine tests. They may have:

* Scans
* Heart, lung, and eye tests
* Lab tests
* Tumor samples taken

Participants will have leukapheresis. Blood will be removed by a needle in an arm. It will go through a machine that removes white blood cells. Plasma and red cells will be returned through a needle in the participant s other arm.

Participants cells will be grown in the lab and genetically changed.

Participants will stay in the hospital 2-3 weeks. There they will:

* Get 2 chemotherapy drugs by catheter (thin plastic tube) inserted into a vein in the chest.
* Get the changed cells via catheter.
* Get a drug to increase white blood cell count and one to make the cells active.
* Recover for about a week.
* Have lab and blood tests.

After leaving the hospital, participants will:

* Take an antibiotic for several months.
* Have leukapheresis.
* Have one- or two-day clinic visits every few weeks for 2 years, and then as determined by their doctor. These will include blood and lab tests, imaging studies, and physical exam.

Participants will have follow-up checks for up to 15 years.

Sponsoring Institute: National Heart, Lung, and Blood Institute

...

Metastatic renal cell carcinoma (RCC) is an incurable condition. Current therapy for this disease consists of the serial administration of agents such as VEGF, mTOR inhibitors and immunotherapy (high-dose (HD) IL-2 or immune-checkpoint inhibitors). Long-term survival can be achieved with high-doses IL-2 or immune-checkpoint inhibitors. However, of those patients treated with immunotherapy, three quarters will not respond at all and only 5-8% will achieve a complete and durable response.

Allogeneic hematopoietic stem cell transplantation is also capable of inducing prolonged disease regression in patients with metastatic clear cell RCC (ccRCC). In vitro studies have established that transplanted donor T-cells targeting antigens expressed on RCC cells mediate these anti-tumor effects. However, hematopoietic stem cell transplantation can be toxic and associated with a 10-20% risk of procedure-related mortality. The observation that transplanted donor T-cells have the potential to cure a subset of patients with metastatic disease forms the basis for continued efforts in our laboratory to harness the power of T-cells to cure this disorder.

Our team isolated a tumor-specific cytotoxic T lymphocyte (CTL) line from peripheral blood mononuclear cells (PBMCs) obtained after an allogeneic transplant from a patient who showed prolonged tumor regression. Using limiting dilution cloning, we identified an allogeneic (derived from the stem cell donor) CD8+ T-cell clone that killed ccRCC cells in an HLA A11 restricted fashion. Using cDNA expression cloning, we identified a HERV-E derived antigen expressed in the patient s ccRCC cells to be the target of this T-cell clone. Remarkably, we found this HERV-E was expressed in the majority of ccRCC cells with no expression in normal tissues. Based on the identification of the antigenicity of the HERV-E transcripts in ccRCC, our team in collaboration with Dr. Nishimura s laboratory (Loyola University Cardinal Bernardin Cancer Center) has cloned, expressed and characterized the TCR from this CD8+ T-cell clone that recognizes an HLA A11 restricted HERV-E antigen.

This research protocol is therefore designed to evaluate the safety and effectiveness of infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells in HLA-A\*11:01 positive patients with metastatic clear cell RCC. Subjects will receive a novel non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide and fludarabine followed by an infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells. To mediate T cell survival and sustain function, moderate-doses of IL-2 (aldesleukin) will be administered intravenously twice a day for 14 doses.

The primary endpoint is safety by day 21. Secondary endpoints will include overall response rate, progression-free survival and overall survival. Exploratory studies will include persistence of circulating HERV-E TCR transduced CD8+/CD34+ enriched T cells, changes in immune cell subsets and activation status of T cells, as well as, other immunologic determinants with clinical outcomes at baseline, at different time points during treatment and at the time of disease progression.

HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma

A Phase I Study of HERV-E TCR Transduced Autologous T Cells in Patients With Metastatic Clear Cell Renal Cell Carcinoma

.Currently the protocol does not specify whether any IPD will be shared. The prospect of IPD sharing is currently under consideration by the PI.

The primary endpoint will be the toxicity profile at each dose level captured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 except for hematological toxicities

Loyola University Medical Center (LUMC)

National Heart, Lung, and Blood Institute (NHLBI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma	NCT03354390	Kidney Cancer	cell infusion	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)
HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma	NCT03354390	Kidney Cancer	cell infusion	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)

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