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Tandem CD20–CD19 CAR T-cell therapy for relapsed B-cell malignancies

Jan 14, 2021
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The novel chimeric antigen receptor (CAR) T-cell therapies targeting CD19 achieved unprecedented survival outcomes in heavily pretreated patients with advanced B-cell malignancies. However, some patients still relapse, mostly with CD19-negative disease, reducing considerably their treatment options left at this stage.

Tandem CAR T cells aim to target two essential antigens widely presented in B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL): CD19 and CD20. Dual targeting might improve the clinical outcomes and overcome antigen-loss relapses seen so far with singly targeted CD19 CAR T-cell therapies.

Nirav N. Shah and colleagues published recently in Nature Medicine the first experience with an onsite manufactured tandem CD19–CD20 CAR T cell for patients with relapsed B-cell malignancies.1 Below there is a summary of the study results.

Study design

  • This is a first-in-human phase I trial to evaluate the safety and feasibility of tandem CD20–CD19 4-1BB–CD3ζ lentiviral (LV20.19) CAR T-cell therapy for patients with relapsed/refractory B-cell malignancies (NCT03019055).
  • A total of 26 patients were enrolled, of which 22 achieved the target dose. The key selection criteria were:
    • Measurable B-cell NHL or CLL, treated with at least two prior lines of therapy.
    • CD19 or CD20 positive disease (≥ 5% by immunohistochemistry or flow cytometry) in the most recent biopsy.
    • CD3-positive T-cell count of at least 50/mm3.
    • Karnofsky performance score ≥ 70.
    • No active central nervous system involvement.
    • Prior CAR T-cell therapy was permitted if patients remained positive for CD19 or CD20.
  • After apheresis and lymphodepletion (30 mg/m2 fludarabine for 3 days and 500 mg/m2 cyclophosphamide for 1 day), patients were divided into three cohorts:
    • Cohort 1: dose escalation at dose levels 2.5 × 105 cells/kg, 7.5 × 105 cells/kg, and a target dose of 2.5 × 106 cells/kg, administered over 2 days (30–70%).
    • Cohort 2: expansion cohort with dose selected from cohort 1, split into a 2-day infusion.
    • Cohort 3: expansion cohort with selected dose, single infusion.

LV20.19 CAR T-cell manufacturing

  • The CliniMACS Prodigy is a new closed-system device that enables the production of CAR T cells locally.2 Tandem LV20.19 CAR T cells were manufactured onsite at the Medical College of Wisconsin.
  • Once adjusted and tested appropriately, it can reduce manufacturing timelines (14 days), and patients can receive fresh CAR T cells (non-cryopreserved).
  • In the cell cultures, a mean of 17.4% were CAR T cells (range, 7.4–28.0%), with a mean CD4:CD8 ratio of 3:1 at the time of cell collection.
  • The final product reached an average of 5.76 × 108 LV20.19 CAR T cells (range, 2.22–12.8 × 108).

Results

  • Patients' baseline characteristics are summarized in Table 1.

Table 1. Patient characteristics at the time of CAR T-cell infusion1

AA, African American; allo, allogeneic; auto, autologous; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; DLBCL, diffuse-large B-cell lymphoma; EA, East Asian; FL, follicular lymphoma; MCL, mantle cell lymphoma; SCT, stem cell transplant.

Characteristic

Patients (N = 22)

Median age, years (range)

57 (38–72)

Race, %

 

   European ancestry

86

   AA, EA, or Native American

14

Lymphoid malignancy, %

 

   DLBCL

50

   MCL

32

   CLL

14

   FL

4

Median lines of prior therapy (range)

4 (2–12)

Refractory to the last line of therapy, %

82

Prior auto-SCT, %

37

Prior allo-SCT, %

14

Patients infused at each dose level, %

 

   2.5 × 105 cells/kg

14

   7.5 × 105 cells/kg

14

   2.5 × 106 cells/kg

73

Split infusion, %

73

Non-cryopreserved cell product infused, %

68

  • Tandem LV20.19 CAR T cells achieved an overall response rate (ORR) of 82% after 28 days from infusion, including high complete response (CR) rates across all subtypes (Figure 1).
  • Higher rates and better responses were achieved in the target dose level cohort and in patients infused with fresh cells; although the difference is not statistically significant (p = 0.08), it is important to note that these patients also presented a higher expansion of the CAR T-cell product.
  • After a median follow-up of 10.1 months, the median duration of response in patients achieving a CR was not reached.
  • To date, nine (40.9%) patients progressed after initial response to LV20.19 CAR T cells; four of them were late relapses (≥ 6 months after infusion). Three patients progressed again after retreatment with the cryopreserved product.

Figure 1. Response rates at Day 28 after infusion of LV20.19 CAR T cells by type of B-cell NHL1

CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse-large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; ORR, overall response rate; PR, partial response; TDL, target dose level.
*2.5 × 106 cells/kg.

  • Patients who were previously exposed to an anti-CD19 CAR T-cell therapy (n = 5) presented lower manufacturing success. Three were infused with the tandem CAR T cells but progressed by Day 28.
  • Split and single infusion cohorts did not differ in response rates or adverse event incidence.
  • Median overall survival was 20.3 months.

Predicting response to LV20.19 CAR T cells

  • Baseline CD19 and CD20 expression was not associated with response to LV20.19 CAR T cells.
  • Responders presented a peak of CAR T-cell expansion in peripheral blood at 7–12 days and were undetectable by Day 90 post-infusion.
  • Higher levels of naïve and central memory T cells in the apheresis product were detected in patients later achieving a partial response or CR at the higher dose level.
  • Five patients with progressive disease were infused with a lower dose level than 2.5 × 106 cells/kg.
  • Biopsies after progression to LV20.19 CAR T cells show persistence of CD19 expression.

Safety

  • There were no dose-limiting toxicities reported in the dose-escalation cohorts, although one patient in the expansion cohort experienced a dose-limiting toxicity at 2.5 × 106 cells/kg, requiring urgent hospitalization due to Grade 4 cytokine release syndrome (CRS) and neurotoxicity.
  • The most frequent Grade ≥ 3 adverse events (AEs) with the higher CAR T-cell dose were cytopenia, hypoxia, and neurotoxicity. See Table 2 for a detailed list.
  • Considering all dose levels, a total of 14 patients (64%) experienced CRS, and seven patients (32%) reported a neurotoxic event of any grade at a median time of 5 and 6 days from infusion, respectively.
  • There were no deaths associated with LV20.19 CAR T-cell therapy.

Table 2. Most frequently reported AEs with LV20.19 CAR T cells at dose 2.5 × 106 cells/kg (n = 16)1

AE, adverse event; ALT, alanine aminotransferase; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; WBC, white blood cell.

AE reported in > 25% of patients

All Grades, %

Grade ≥ 3, %

Lymphocytopenia

88

88

Decrease in WBCs

88

75

Neutropenia

81

69

Anemia

75

44

CRS

75

6

Hypocalcemia

63

6

Thrombocytopenia

56

31

Increased creatinine

44

6

ALT increased

38

6

Neurotoxicity

31

19

Conclusion

This first-in-human study reported the feasibility and safety of dual-targeting CD19 and CD20 with the tandem CAR T-cell therapy LV20.19 for patients with relapsed or refractory B-cell malignancies. With the possibility of onsite manufacturing, timelines were optimized, and it was possible to infuse non-cryopreserved product at 2.5 × 106 cells/kg, which led to a potentially better expansion of the CAR T cells, hence, a possibility to improve the clinical outcomes. This local procedure had an 85% success rate, including the 100% of patients naïve to CAR T cells, but needs to be further investigated.

In light of the promising response rates, the phase I/II trial with LV20.19 in B-cell NHL and mantle cell lymphoma has already started to recruit participants (NCT04186520), including patients previously treated with CD20-directed therapy and anti-CD19 CAR T-cell therapy.

A similar strategy with the same device has been tested in the University Hospital Cologne, Germany, by Peter Borchmann and colleagues. The initial results of the MB-CART2019.1 tandem CAR T-cell therapy in relapsed/refractory B-cell NHL were presented recently at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. Watch below a summary of the phase I trial results, which, so far, are consistent with the ones reported with LV20.19.

Results from the phase I study of a novel CD19/CD20 tandem CAR T-cell therapy in R/R B-cell NHL

  1. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569-1575. DOI: 1038/s41591-020-1081-3
  2. Zhu F, Shah N, Xu H, et al. Closed-system manufacturing of CD19 and dual-targeted CD20/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. Cytotherapy. 2018;20(3):394-406. DOI:1016/j.jcyt.2017.09.005

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