Genetically Engineered T Cells Show Promise in B Cell Malignancies

Roxanne Nelson

December 15, 2011

December 15, 2011 (San Diego) — Results from a small early-stage study reveal a promising new treatment strategy for B cell malignancies  — one  using genetically engineered T cells.

Of the 8 men who received infusions of autologous T cells that were transduced with gamma-retroviruses encoding an anti-CD19 chimeric-antigen receptor (CAR), 6 experienced remissions. However, the researchers note that because the patients received chemotherapy prior to the T cell infusions, the contribution of CAR-transduced T cells to the remissions is unclear.

The study was presented here at the American Society of Hematology 53rd Annual Meeting.

"Administration of genetically modified T cells is an exciting area of cancer research because early results from many clinical trials have demonstrated the potent anticancer activity of T cells," explained lead author James N. Kochenderfer, MD, assistant clinical investigator at the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI) in Bethesda, Maryland.

"The approaches used in genetically modified T cells can be rapidly changed and tested, so rapid progress in this field is anticipated," he added.

New therapies are needed for patients with B cell malignancies who have developed resistance to chemotherapeutic agents, and CD19 is an appealing target antigen because its expression is limited to normal B lineage cells and B cell malignancies. Therefore, the transfer of T cells that are genetically engineered to express CARs that specifically recognize the B cell antigen CD19 has promise as a treatment strategy for B cell cancers, explained Dr. Kochenderfer.

Remissions and Responses

In this study, Dr. Kochenderfer and researchers from the NCI and the Odette Cancer Center at the Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, used gene therapy to induce patient-derived T cells to express anti-CD19 CAR-encoding genes. The goal was for the T cells to recognize and destroy the B cell lymphomas and leukemias that express CD19.

The clinical protocol consisted of cyclophosphamide (60 mg/kg for 2 doses) plus fludarabine (25 mg/m² for 5 doses) chemotherapy followed by an autologous infusion of anti-CD19 CAR-transduced T cells and a course of high-dose interleukin-2 (720,000 IU every 8 hours to tolerance, with a maximum of 15 doses). A gamma-retroviral vector encoding an anti-CD19 CAR was synthesized.

"We found that the chemotherapy can enhance the activity of the infused T cells, so that is why it was infused first," said Dr. Kochenderfer.

He also pointed out that all of the patients in the trial had progressive disease and had undergone at least 3 previous therapies.

The CAR used in the trial was comprised of variable regions of an anti-CD19 antibody, a portion of the CD28 molecule, and a portion of the CD3-zeta molecule.

Of the 8 patients  in the trial, 4 had chronic lymphocytic leukemia (CLL) and 4 patients had B cell lymphoma. All patients were infused with anti-CD19 CAR-transduced T cells that specifically recognized CD19-expressing target cells. The total number of cells administered to each patient ranged from 0.5 ₓ 107 to 5.5 ₓ 107 cells/kg of bodyweight. Of the cells administered, a mean of 54% expressed the anti-CD19 CAR.

The number of responses was encouraging. "Six of the 8 patients treated obtained a partial or complete remission, and 4 of the 6 remissions are ongoing at this time," said Dr. Kochenderfer.

One patient with CLL has now been in complete remission for 15 months. Of the 5 patients who achieved partial remissions, 3 are ongoing. One patient with CLL achieved stable disease; one lymphoma patient died of culture-proven influenza A pneumonia, and thus the response could not be evaluated.

Patient Characteristics and Response

Patient Age (y) Previous
           treatments (n)
Disease Duration of Response
1a* 474Follicular lymphomaPartial response, 7 m
1b* 485Follicular lymphomaPartial response, 18+ m
2 485Follicular lymphomaN/A (died)
3 613CLLComplete response, 15+ m
4 553Splenic marginal zone lymphomaPartial response, 12 m
5 544CLLStable disease, 6 m
6 577CLLPartial response, 7 m
7 614CLLPartial response, 7+ m
8 637Follicular lymphomaPartial response, 8+ m
*Patient 1 was treated twice

High Toxicity Observed

Dr. Kochenderfer noted that although these results are positive, the treatment caused significant toxic effects — the most prominent being hypotension. Other prominent toxic  effects included fatigue, fevers, and acute temporary renal failure.

There were sharp elevations in serum interferon gamma (IFN) and in tumor necrosis factor (TNF) in 4 patients in the first 10 days after cell infusion. In the 4 patients with prominent elevations in inflammatory cytokines, the peak serum IFN levels ranged from 865 to 2305 pg/mL and the peak TNF levels ranged from 49 to 118 pg/mL. The 4 patients with these high increases in IFN and TNF experienced more severe clinical toxicity in the first 10 days after therapy than the rest of the cohort.

In an analysis of the peripheral blood mononuclear cells (PBMC) of 3 patients with high levels of serum IFN and TNF, the researchers "detected T cells that produced IFN and TNF in a CD19-specific manner in PBMC samples collected after anti-CD19 CAR-transduced T cell infusions, but not in PBMC samples collected before CAR-transduced T cell infusions."

"This indicates that anti-CD19 CAR-transduced T cells were a source of the elevated serum cytokines," they write.

This study presented data from a very important area of research — that of modifying T cells, said Martin S. Tallman, MD, chief of the leukemia service at the Memorial Sloan-Kettering Cancer Center in New York City. "They are also now directed at specific B cell malignancies."

"Certainly, this represents intellectual advances and may represent potential changes in the way we take care of patients," said Dr. Tallman, who moderated a press briefing during which the highlights of this study were presented.

The authors have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 167. Presented December 11, 2011.


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