Fred Hutchinson Cancer Center is home to some of the world’s most advanced cancer treatments, including CAR T-cell therapy for post-transplant lymphoproliferative disorder (PTLD). Physicians in the Cancer and Organ Transplant Clinic (COTC) at Fred Hutch recently published a report of a patient who became the 17th in the world to receive this life-saving therapy.
Physicians of COTC successfully used CAR T-cell therapy to treat a patient with PTLD. The 47-year old patient, who had three kidney transplants over 34 years, was the 17th in the world to receive this innovative treatment. A case report and systematic review, published recently in Bone Marrow Transplantation, details the treatment and positive outcomes.
“Until recently, the use of CAR T-cell therapy for PTLD had been largely unknown,” says Christopher Blosser, MD, COTC director. “Aggregated data from our case and the 16 previously published reports show this treatment is safe and effective. CAR T-cell therapy does not appear to cause organ rejection and has limited side effects when compared to other chemotherapies and immunotherapies.”
What is PTLD?
PTLD is usually caused by the oncogenic Epstein-Barr virus (EBV). EBV is a common viral infection that causes mononucleosis. After infection, the virus incorporates itself into the DNA of B-cell lymphocytes and can affect the mechanisms controlling B-cell death. A healthy immune system keeps proliferating B cells in check. For people receiving immunosuppression therapy to prevent transplant rejection, the buildup of B cells may lead to lymphoma.
About 80% of PTLD cases are EBV-related diffuse large B-cell lymphoma (DLBCL). Less often, other oncogenic viruses cause T-cell lymphoma or Hodgkin lymphoma PTLD.
Most adults are exposed to EBV at some point in their life. Naïve transplant patients (without past EBV infection) have twice the risk of PTLD than patients with a history of EBV infection. The source of EBV infection in naïve patients is usually the transplanted organ. The onset of PTLD after transplant is also faster for naïve patients (within the first year) vs. previously exposed patients (5 to 10 years), says Blosser.
Standard treatments for PTLD
The first-line therapy for PTLD is to decrease immunosuppression medications so the patient’s immune system can kill the cancer cells. The effectiveness of this approach varies, depending on the extent of the lymphoma.
Rituximab, alone or with other medications, is the second-line option. Rituximab is a monoclonal antibody that attaches to B cells, marking them for destruction by the immune system. Combination treatments include:
- R-CHOP: Rituximab, cyclophosphamide, hydroxydaunomycin, Oncovin® and prednisone
- RICE: Rituximab, ifosfamide, carboplatin and etoposide
“These two lines of therapy are effective for about 80% of patients,” says Blosser. “The remaining 20% have refractory or resistant PTLD. The mortality rates in these patients are markedly high and the options are quite limited.”
The two treatment options for refractory or resistant PTLD include:
- Autologous stem cell transplant: This procedure involves removing stem cells from a patient’s blood, growing them in a laboratory and giving them back to the patient. Chemotherapy given before the stem cell transplant destroys lymphoma cells and bone marrow. The transplanted stem cells restore the bone marrow.
- Chimeric antigen receptor (CAR) T-cell therapy: This therapy entails removing a patient’s T cells (e.g. leukapheresis). A laboratory modifies the T cells to produce surface receptors (CARs) that recognize specific proteins on B cells, in the case of PTLD. The laboratory makes millions of copies of the CAR T cells, which the patient receives through an infusion after receiving chemotherapy to prevent killing CAR T cells or a systemic reaction. The CAR T cells activate an immune response against the lymphoma.
Case report
The patient received an initial kidney transplant and lymphoma care in the community. Blosser met the patient 3 months before CAR T-cell therapy when the initial PTLD treatment did not work. The patient was 47 years old and nine years into his third kidney transplant. His kidney function was good, but he had lost weight and was experiencing night sweats and back pain. An MRI revealed multiple cancer points, including the lymph nodes and bones. A biopsy confirmed the diagnosis of PTLD.
Reducing immunosuppression and six cycles of R-CHOP achieved only partial remission, followed by a recurrence of symptoms. Salvage therapy with RICE was also ineffective and caused significant side effects. The team considered autologous stem cell transplant, but the patient’s disease progressed.
“The patient was so weak, we didn’t think he would survive the stem cell transplant,” says Blosser. “The only remaining option was CAR T-cell therapy.”
The first challenge was to collect enough T cells. Blosser stopped the patient’s immunosuppression medications about six weeks before leukapheresis. To prevent a reaction to the CAR T cells, the team gave him immunosuppressing medications and chemotherapy for about a month before receiving the CAR T cells. The patient did well through these steps and achieved remission in three months. At this point, Blosser added a second immunosuppression medication to the low-dose steroid the patient was on to prevent kidney transplant rejection.
About eight months after CAR T-cell transplant, the patient developed pain in the hip. A scan showed a mass which, upon biopsy, turned out to be lymphoma. He had no lymphoma in his bloodstream, so the team treated the mass with radiation therapy. Over a year later, the patient remains in complete remission, and has not experienced rejection throughout the treatment course. Blosser’s team follows the patient monthly and orders CT scans every three months.
The future of CAR T-cell therapy in PTLD
CAR T-cell therapy is advancing rapidly, with new applications emerging for other blood cancers and solid tumors. As research produces better outcomes, CAR T-cell therapy may move up in the treatment hierarchy.
Blosser and his colleagues at Fred Hutch participate in ongoing research into CAR T-cell therapy for PTLD. “We have a great core of immunotherapy scientists and clinicians,” he says. “They are working to identify better targets on lymphoma cells and personalize those targets based on a person’s type of cancer. Researchers are also seeking CAR T cells that live longer, cause fewer side effects and cost less.”
Cancer care in patients with organ transplant at Fred Hutch
The COTC at Fred Hutch is the first of its kind, and provides a novel, unified approach to cancer and transplant care. The COTC serves people with PTLD and many other cancers before and after organ transplant. Seemingly simple yet complex in execution, each patient sees cancer and transplant specialists specific to their condition during the same visit. The specialists review the case and discuss the patient’s concerns and goals, and then a real-time tumor/transplantation board meets to develop a recommended treatment plan. Immediately after this meeting, the specialists share their recommendations with the patient and referring providers, and the patients are provided an audio recording of the discussion related to the specialists’ recommendations to take home.
COTC specialists also coordinate closely with community physicians. Blosser recommends patients have at least one visit in the clinic. “More often than not, at least one appointment can help facilitate optimal steps in a patient’s care,” he says. “And the earlier we meet that patient, the more likely we can help improve their outcomes.”
To consult with Blosser or another COTC specialist, call 800.4UW.DOCS or explore our physician resources.
For patient referrals, contact:
- Phone: 206.606.8300
- Fax: 206.606.2216
