Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

Abstract

Patients with Burkitt lymphoma who are refractory to initial therapy or who relapse after undergoing intensive chemotherapy and autologous stem cell transplantation (ASCT) usually have a poor prognosis. While there has been considerable progress in the use of chimeric antigen receptor-modified (CAR) T cell immunotherapy for the treatment of relapsed and refractory (r/r) malignancies, explicit data on adult patients with r/r Burkitt lymphoma are limited. We conducted two single-arm clinical trials to evaluate the clinical efficacy and toxicity of CD19/CD22 CAR T cell immunotherapy both alone (trial A) and in combination with ASCT (trial B) in adult patients with r/r Burkitt lymphoma. In total, 28 adult patients with r/r Burkitt lymphoma were enrolled [trial A (n = 15) and trial B (n = 13)]. The median doses of CD22 and CD19 CAR T cell infusions were 4.1 × 10⁶/kg and 4.0 × 10⁶/kg, respectively. Subsequently, after CAR T cell infusion, overall and complete responses were observed in 19 (67.9%) and 16 (57.1%) patients, respectively. The cumulative incidence rates of grade 2-4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were 39.3% (11/28) and 10.7% (3/28), respectively. After a median follow-up duration of 12.5 months, 16 patients (5 in trial A and 11 in trial B) survived. Both the estimated 1-year progression-free and overall survival rates were 55.6%. Our preliminary results indicated that salvage therapy with CD19/CD22 CAR T cell infusion alone and that in combination with ASCT are effective in treating some adult patients with r/r Burkitt lymphoma.

Keywords: Burkitt lymphoma; chimeric antigen receptor; cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; immunotherapy; transplantation.

Figure 1

Participant screening flow chart. Adult patients with r/r Burkitt lymphoma who opted to undergo CAR T cell immunotherapy or CAR T cell immunotherapy combined with ASCT entered the screening progress. All participants were r/r after prior treatments (therapy lines ≥ 2). The positive expression of CD19 and CD22 was confirmed via flow cytometry or immunohistochemical analysis. Measurable diseases, normal organ function, and good performance status were necessary for inclusion. Patients with uncontrollable infections were excluded. Patients with enough autologous HSCs were included in trial B and those without enough autologous HSCs were included in trial A. ASCT, autologous stem cell transplantation; CAR, chimeric antigen receptor; HSC, hematopoietic stem cell; r/r, refractory/relapsed; trial A, CD19/CD22 CAR T cell immunotherapy; trial B, CD19/CD22 CAR T cell immunotherapy following ASCT.

Figure 2

Probabilities of OS and PFS of adult patients with r/r Burkitt lymphoma enrolled in our study. (A, B) The estimated 1-year PFS and OS of all participants were 55.6% (95%CI: 35.2–71.8%) and 55.6% (95% CI: 35.2%–71.8%), respectively. (C, D) The estimated 1-year PFS rates of the patients in trial A and trial B were 33.3% (95% CI: 12.1%–56.4%) and 83.3% (95% CI: 48.2%–95.6%), respectively (p = 0.01), which were the same as the 1-year OS rates. OS, overall survival; PFS, progression-free survival; r/r, refractory/relapsed. *The comparison was considered statistically significant.

Figure 3

Factors associated with CRS. (A) Peak serum IL-6 levels were significantly higher in patients with grade 2–4 CRS than in patients with grade 0–1 CRS. (B-D) No significant differences were observed between serum ferritin levels, CAR T cell infusion doses, and CRS severity. CRS, cytokine release syndrome; IL-6, interleukin-6; CAR, chimeric antigen receptor. *The comparison was considered statistically significant.

Figure 4

CAR T cell kinetics in adult patients with r/r Burkitt lymphoma enrolled in our study. (A, B) The median peak levels of CD22 and CD19 CAR T cell lentivirus copies in our study patients were 6951 (range: 141–39503) and 3930.5 (range: 125–69036) copies/µg DNA, respectively. (C-F) The median peak levels of CD22 and CD19 CAR T cell lentivirus copies were 2627 (range: 141–39503) and 1898 (range: 130–32422) copies/µg DNA, respectively, in trial A; and 9724 (range: 1000–30034) and 3939 (range: 125–69036) copies/µg DNA, respectively, in trial (B) CAR, chimeric antigen receptor; r/r, refractory/relapsed.

Figure 5

Association between CAR T cells and objective response. (A) The poor expansion of CD19 CAR T cells in vivo was associated with unsatisfactory efficacy. (B-D) There were no statistically significant correlations between CD22 CAR T cells expansion levels, CAR T cell infusion doses, and objective response. CAR, chimeric antigen receptor; CR, complete response; PD, progression of disease; PR, partial response; SD, stable disease. *The comparison was considered statistically significant.