Researchers Aim to Improve Blood Cancer Outcomes With Engineered T-Cell Treatments

Merav Bar, MD

Assistant Member, Clinical Research Division, Fred Hutchinson Cancer Research Center

Assistant Professor, Medical Oncology Division, University of Washington

Researchers at the Seattle Cancer Care Alliance (SCCA) have optimized special methods for modifying T cells to target specific cancer cells in patients with blood cancers. These new T-cell therapies are primarily being tested in clinical trials involving patients with highrisk leukemia or lymphoma before or after bone marrow transplant (BMT).

Preventing Relapse in Adults After Allogeneic BMT for Lymphoid Malignancies

Approved by the FDA last year, CD19-specific Donor T Cells for B-Cell Malignancies After Allogeneic Transplant is a phase I/II trial designed to boost the graft-versus-tumor effect in subgroups of adults with acute lymphocytic leukemia, chronic lymphocytic leukemia, or diffuse large B-cell lymphoma who have received an allogeneic BMT from a matched related donor, thereby reducing the risk of posttransplant relapse.

After their transplant, patients will receive engineered T cells, generated from the donor’s blood. A lentiviral vector inserts a gene that encodes a chimeric antigen receptor (CAR), which is half monoclonal antibody and half T-cell receptor, that targets the CD19 molecule expressed exclusively on B cells (both malignant and normal). CARs are hard-wired to bind to the tumor cell without regard to the patient’s HLA status. This is important because it allows a single pre-constructed CAR to target tumors in patient populations with diverse HLA patterns. Once they bind to the target, the T cells automatically trigger cytotoxicity.

“We are coupling the exquisite specificity of the antibody to the potent effector functions of the T cell,” said Stanley R. Riddell, MD, oncology and immunology researcher at Fred Hutchinson Cancer Research Center. “We target the tumor with the antibody and kill it with the T cell. Moreover, since this is a living therapy, the engineered cells can grow in the patient until the tumor is eradicated.”

SCCA researchers enrich the donor’s T-cell population with longer-lasting central memory cell subsets to encourage the T cells to persist in the patient.

Engineered T-cell therapy has potential for the treatment of patients with B-cell malignancies, but more work is needed to make the responses durable. Using central memory cells as a starting population for expansion might enable transferred T cells to provide long-lasting antitumor effects.

Preventing or Treating Relapse After BMT for AML, MDS, or CML

This phase I/II trial has two arms: (1) prophylactic T-cell therapy for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML) patients with high risk of relapse after BMT, and (2) treatment with T cells for AML/MDS/ CML patients with either minimal residual disease or full hematologic relapse after BMT.

The strategy involves genetically engineering donor-derived T cells to express a T-cell receptor specific to WT1, a protein that is highly expressed on leukemia cells. The magnitude of WT1 expression correlates with the cancer’s aggressiveness. The gene that encodes the high affinity WT1 T-cell receptor has been isolated from a healthy individual with human leukocyte antigen (HLA)-A*0201 and cloned into a lentiviral vector, which is then used to transduce donor-derived T cells. For this to work, the patient must have the proper matching HLA-A*0201 marker.

This HLA marker was chosen because it is common in the overall population, seen in about a third of Caucasians. Eventually an array of lentiviral vectors will allow treatment of any HLA type.

Researchers targeted the WT1 antigen based on a recent SCCA study (Sci Transl Med. 2013;5[174]:174ra27) showing antileukemic activity without significant main organ toxicity or graft-versus-host disease in patients receiving WT1-specific donor-derived CD8+ cytotoxic T cells after BMT for high-risk leukemia. These were not engineered but naturally occurring anti-WT1 T cells that were carefully isolated from the donor’s lymphocytes, grown in culture, and given to the patient. At the time of the study’s publication, four patients with the best responses were still alive with no recurrence of their cancer more than 2 years after transplant.

The prior donor-derived WT1-specific T-cell study has great variability in the function of the T cells from the different donors. For our new study, genes for the anti-WT1 T-cell receptor from a healthy donor whose T cells led to the best antileukemic activity in the laboratory were cloned into a lentiviral vector now used to engineer donor T cells in this trial. We hope that by using this new strategy, all patients will receive T cells with better function.

Variations on the T-Cell Theme

The array of immunotherapy approaches being developed at SCCA could provide important new options for many difficult-to-treat cancers.

There are countless variations on engineered T-cells, and more emerge every day. T-cell therapies are carefully tested in patients with specific forms of high-risk leukemia or lymphoma either before or after BMT. If early tests go well, T-cell treatments may be created for lower-risk disease or other types of hematological or solid cancers. Whether deployed in conjunction with stem-cell transplantation or used as a stand-alone cancer therapy, genetically modified T cells are a promising treatment for patients who have few other treatment options.

Overview of Cancer Immunotherapy With Engineered T Cells

In T-cell immunotherapy, a patient’s T cells are purified, reprogrammed with recombinant DNA, and grown in a special laboratory. The reprogramming instructs the T cells to make a receptor that recognizes a tumor-specific protein (possibly a special chimeric antigen receptor). When the engineered cells are infused into the patient, they hunt down and eradicate the cancer cells and remain in the bloodstream as memory cells to provide long-term protection.

Figure courtesy of Stanley R. Riddell, MD, oncology and immunology researcher at Fred Hutchinson Cancer Research Center

Note: The entry criteria and timelines for these trials may change, and several new trials are still being designed, so referring physicians with high-risk leukemia or lymphoma patients who may benefit should contact SCCA for up-todate information.