1. May, Brandon

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In patients with aggressive and hard-to-treat hematologic malignancies, one of the most promising areas of clinical research focuses on chimeric antigen receptor (CAR) T-cell therapy for prolonging survival and improving patient outcomes.

CAR T cells; diffuse... - Click to enlarge in new windowCAR T cells; diffuse large B-cell lymphoma. CAR T cells; diffuse large B-cell lymphoma

A case study recently reported in The New England Journal of Medicine has shown that CAR T-cell therapy was effective for inducing complete remission of a brain metastasis of a tumor diffuse large B-cell lymphoma (DLBCL) in a 68-year-old female chemotherapy-refractory patient. This case study, according to the investigators, represents one of the first reports of a benefit of CAR T cells in a central nervous system lymphoma (2017;377(8):783-784).


DLBCL: Definition, Signs, & Prognosis

The B cells, a class of antibody-generating white blood cells, is the main cell type affected in DLBCL. As such, DLBCL generally produces B-type symptoms, including fever, night sweats, and weight loss. Approximately 30-40 percent of adult non-Hodgkin lymphomas are diagnosed as DLBCL (Ann Oncol 2014;25(11):2124-2133).


The first sign of this type of cancer is often the appearance of a large mass, which can generate in virtually any area of the body. While normal DLBCL is often aggressive, refractory or relapsed DLBCL is particularly more threatening and associated with significantly poor prognosis. In fact, the median overall survival is around 4.4 months among patients achieving no benefit from second-line salvage therapy, whereas the 1-year survival is approximately 23 percent in these same patients (Bone Marrow Transplant 2016;51(1):51-57).


"Brain involvement in DLBCL carries a grave prognosis, and the ability to induce a complete and durable response with conventional therapies is rare," according to a previously published statement by lead investigator and author Jeremy Abramson, MD, of the Massachusetts General Hospital Cancer Center, Boston.


Since this form of high-grade, rapidly-growing lymphoma is associated with dismal survival rates, early treatment may be key for reducing mortality. Treatment often includes the combination of rituximab and CHOP chemotherapy (R-CHOP), the latter of which usually consists of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (Blood 2015;125(12):1866-1869).


Typically, this standard form of treatment for DLBCL provides the most efficacy when administered several times over a span of 4 or more months. Elderly patients with DLBCL have experienced the most benefit from this regimen, with previous research showing that the R-CHOP treatment strategy may increase the rate of complete response and overall survival (J Clin Oncol 2006;24(19):3121-3127, J Clin Oncol 2005;23(18):4117-4126).


Some single-center studies using anti-CD19 CAR T cells (a CAR T-cell therapy depends upon the patient's own genetically engineered T cells and targets specific antigens on cancer cells) in refractory DLBCL have reported a complete remission of greater than 50 percent (J Clin Oncol 2015;33(6):540-549, Sci Transl Med 2016;8(355):355ra116).


Case Study: Refractory DLBCL Treated With CAR T Cells

Upon entering a phase I clinical trial focused on JCAR017, a CD19-directed CAR T-cell product that directly targets the CD19 protein on many B-cell lymphomas, the patient was reported to be refractory to infusional chemotherapy, dose-adjusted doxorubicin, etoposide, and cyclophosphamide in addition to prednisone and vincristine with rituximab. Her disease was also refractory to four other lines of therapy, including stem cell transplantation. The patient was not receiving any immunosuppressive therapy at the time of enrollment.


During the study, the patient was administered JCAR017 following lymphodepleting fludarabine-cyclophosphamide. Neurotoxic effects and cytokine release syndrome were not observed during or after therapy. One month after treatment, a brain MRI and restaging PET-CT demonstrated complete disease remission. Restaging scans at 2 months, however, revealed recurrent subcutaneous disease, and an incisional biopsy was performed. When the subcutaneous tumor appeared and the biopsy was performed, researchers noticed that the numbers of CAR T cells spontaneously re-expanded, culminating into the regression and remission of the tumor.


More than a year after the CAR T-cell therapy, the patient did relapse and die. The investigators noted, however, that the brain tumor never did recur during this period. These findings demonstrate the association between CAR T-cell therapy and prolonged survival in a DLBCL patient refractory to standard therapy. Considering that many patients in this situation have a mortality rate of 6 months or less following diagnosis, this case study provides innovative insight into the role of these therapies, specifically JCAR017, with advanced DLBCL.


Applicability & Relevance for Clinical Practice

Patient understanding of CAR T-cell therapy is lacking, and many patients do not realize these new therapies may be available. "It is very important for patients and their loved ones to understand this emerging new treatment paradigm and its practical use in lymphoma so that they can become their own health advocate," noted Meghan Gutierrez, Chief Executive Officer at the Lymphoma Research Foundation.


Here, Gutierrez and colleagues are active in helping lymphoma patients understand CAR T-cell therapy as a potential treatment option for DLBCL. "[We're] evaluating how we can best serve lymphoma patients during this period," noted Gutierrez, "including answering their questions about access to CAR T-cell therapies, the associated costs, and implications on their quality of life."


Clinical trials related to CAR T cells for lymphoma management, according to Gutierrez, represent one area in which awareness needs to be maximized in order for patients to understand their available treatment options. In some cases, investigational drugs and clinical trials may be their only options.


The patient in this case study entered a clinical trial which sought to determine the effect of JCAR017. Since the study produced somewhat favorable results in terms of longer overall survival, there is now a greater rationale for further clinical research focused on patients with refractory and advanced disease.


Although CAR T-cell therapy represents an exciting and hopeful new area of research, some limitations exist. "Scientists are still in the early stages of testing and utilizing this new therapy," explained Gutierrez. In addition, improved understanding of "the efficacy [of CAR T cells] and appropriate targeting of these treatments, as well as the management of treatment-related side effects, are all important areas of continued study."


Investigators' Conclusions

This new and unique case presents further evidence of the practical utility and complete remission potential of CAR T-cell therapies, specifically JCAR017, in a patient with primary refractory DLBCL involving the brain parenchyma. Investigators of this case study report that the response of the central nervous system was durable and resulted in ongoing remission at 1 year. Additionally, the researchers report having "identified anti-CD19 CAR T cells in the cerebrospinal fluid, confirming the ability of these cells to cross the blood-brain barrier."


Abramson further discussed how his findings have expanded upon the current literature regarding CAR T cells in B-cell lymphoma in a recent statement: "In addition, all available CAR T-cell trials have excluded patients with central nervous system involvement. This result has implications not only for secondary DLBCL, like this case, but also for primary central nervous system lymphoma, for which treatment options are similarly limited after relapse and few patients are cured."


Another important finding that must be emphasized is the re-expansion ability of anti-CD19 CAR T cells and the ability of the cells to "re-exert antitumor activity" in vivo several months following infusion. According to the investigators, "The effector cells were present at the time of the recurrence, and something about the biopsy procedure triggered their re-expansion and activation when the presence of the tumor cells alone was insufficient." The researchers theorize that further augmentation of the therapy's efficacy depends upon the discovery of strategic methods for reactivating CAR T cells.


"Typically, the drugs we use to fight cancer and other diseases wear off over time," Abramson adds. "This spontaneous re-expansion after biopsy highlights this therapy as something entirely different, a 'living drug' that can re-expand and proliferate in response to biologic stimuli."


Brandon May is a contributing writer.