Adoptive Immunotherapy for Leukemia and Lymphoma

Published in 2010, this Penn Clinical Briefing™ has been updated to include links to study findings.

Almost a decade prior to the approval of KYMRIAH™ (tisagenlecleucel), researchers at Penn Medicine initiated a clinical trial to evaluate the efficacy and safety of CTL-019 in patients with relapsed or chemotherapy-refractory chronic lymphocytic leukemias (CLL) and acute lymphoblastic leukemias (ALL). The trials results are available at clinicaltrials.gov identifier: NCT01029366.

Called "CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy," the trial was led by researchers Carl June, MD, and David Porter, MD, at Penn Medicine, to assess the efficacy and safety of CTL-019 (formerly known as CART-19), an agent comprised of autologous T cells engineered to express an antibody against CD19.

Among the highly attractive therapeutic targets for the treatment of leukemia and lymphoma , CD19 is an antigen expressed only on the surface of B cells (both normal and malignant) and can thus be used to target B cell lymphomas and leukemias, including ALL, CLL and most non-Hodgkin’s lymphomas. The virtual absence of CD19 in normal tissues and pluripotent blood stem cells limits the potential for induction of autoimmune disease and irreversible myelotoxicity among therapies targeting CD19.

The T cells are genetically modified with a chimeric antigen receptor (CAR) that contains an extracellular single chain antibody (scFv) against CD19 and a potent intracellular signaling domain (the CD3-zeta domain and the 4-1BB fragment of CD137 co-stimulatory receptor) that induce potent T cell activation.

A primary objective of the study was to determine the survival of the redirected autologous T cells transduced with the anti-CD19 lentiviral vector. Study participants included adult patients aged >18 with CD19+ B cell malignancies and no available curative treatment options (such as autologous or allogeneic stem cell transplantation) who had limited prognosis (several months to less than 2 years survival) with currently available therapies.

Preliminary results of the trial were published in the New England Journal of Medicine and Science Translational Medicine in 2011. Subsequent reports related to this study appeared in 2013 and 2015.

Case Study

This image shows the pretreatment (A) and post-treatment (B) bone marrow of a patient with chronic lymphocytic leukemia who received CART-19 therapy. — **Figure 1:** Bone marrow biopsy specimens. [A] Before CART19-cell infusion (baseline); [B] Day 31 (hematoxylin and eosin). At baseline [A], bone marrow demonstrated greater than 50% involvement by chronic lymphoid leukemia (CLL). Day 31 [B] bone marrow shows no evidence of CLL as measured by flow cytometry, cytogenetics and FISH.

Mr. C, 65-year-old male, was diagnosed with CLL four years before he came to Penn. During that time, he had six treatments, all with partial responses, and was now refractory to purine analogs. At Penn, his lab work revealed a white count of 30,000, extensive marrow infiltration and diffuse adenopathy. After a consultation, Mr. C agreed to the CTL-019 treatment regimen.

Mr. C first received a lymphodepleting conditioning regimen consisting of cyclophosphamide (250 mg/m2/d x 3 days) and fludarabine (25 mg/m2 x 3 days) prior to adoptive transfer of T cells. Subsequently, he was administered CTL-019. He then experienced flu-like symptoms, fever, rigor, transient hypertension and tumor lysis syndrome for 14 days. These symptoms resolved over the next two weeks.

Lab tests at his first disease assessment on day 31 revealed that his CTL-019 cell count had expanded by 3 logs; his white cell count was normal; his bone marrow revealed no CLL by deep sequencing (a technology with the capacity to detect the one cell in 100,000 that is cancerous); and his adenopathy had resolved. He was judged to be in complete remission. It is known now that remissions can be sustained for at least two years, and the CTL-019 cells are still circulating in the body at this time. At six months, Mr. C showed no signs of disease.

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Published on: January 2, 2020

References

CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy | ClinicalTrials.gov Identifier: NCT01029366

About Penn Hematology/Oncology

Investigators with Penn Hematology/Oncology are focused on translating laboratory work into novel therapies and practice-changing discoveries. The scope of Penn’s hematology and medical oncology clinical research enterprise is very broad, spanning all phases of clinical research, including pre-clinical work and discovery, phase 1 and 2 studies and leadership of national phase 3 trials intended to change the standard of care.

Penn clinical investigators regularly publish high profile and important findings in diverse fields, ranging from the most fundamental cellular investigations, to leading edge translational and clinical research.