DLBCL,   CLL/SLL,  FL,  MCL,  MZL

CD19/CD22-targeted CAR T therapy for relapsed/refractory B-cell malignancies

Chimeric antigen receptor (CAR) T-cell therapy is under investigation for the treatment of several hematological malignancies. Currently, the only United States (U.S.) Food & Drug Administration (FDA) and European Medicines Agency (EMA) approved indications for CAR T are diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). Many of the CAR constructs being investigated in clinical trials for the treatment of B-cell malignancies target CD19.1-4 However, malignant B cells have developed mechanisms to evade immunotherapies that target specific antigens such as CD19. These include mutation, alternative splicing, protein misfolding of CD19 or myeloid lineage switch of CD19-positive malignant cells. Antigen escape can lead to relapse following CD19-targeted therapies and these patients have poor outcomes.

One proposed method of reducing antigen escape, and subsequently lowering relapse rates, is to infuse two single-specific CAR T products against different antigens. Na Wang, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, CH, and colleagues, therefore conducted a pilot study (ChiCTR-OPN-16008526), in 89 patients with relapsed/refractory (R/R) B-cell malignancies, using two CAR T products administered sequentially.5

The Lymphoma Hub previously covered CAR T therapy as an educational theme. Read more here.

Study design5
  • Open label, single center, single-arm pilot study
  • Aim: evaluate efficacy and safety of sequential infusion of two single-targeted CAR T products (anti-CD19 and anti-CD22)
  • CAR constructs:
  • Third generation CAR
  • Single chain variable fragment from a murine monoclonal antibody against CD19 or CD22
  • Two costimulatory domains: CD28 and 4-1BB
  • Activation domain: CD3ζ
Patient characteristics5
  • Patients with R/R B-cell malignancies screened: 105
    • Sixteen patients did not receive the CAR T product due to production failure, serious infection, withdrawal of consent and disease progression (PD)
    • In total, 84.4% (n=89) of patients who were screened received the CAR T infusions
    • ALL; n=51
    • Non-Hodgkin lymphoma (NHL); n= 38
      • All patients had aggressive clinical disease
      • Twenty-three patients had relapsed three or more times, or had primary refractory disease
  • Median age (total cohort): 36 years (range: 9–71)
Lymphodepletion chemotherapy and CAR T manufacturing and infusion
  • Lymphodepletion chemotherapy given for three days (days -4 to -2):
    • Fludarabine: 25mg/m2
    • Cyclophosphamide: 300mg/m2
  • The two CAR T-cell products were separately infused on successive days from day 0 (81% of patients received anti-CD22 CAR T cells first) and were generally given in two divided doses
    • Median manufacturing time:
      • Anti-CD19 CAR T product: 12 days (range: 8–20)
      • Anti-CD22 CAR T product: 13 days (range: 9–22)
    • Dosing of CAR T products for patients with B-cell NHL:
      • Anti-CD19 CAR T product: 5.1 ± 2.1 ×106/kg
      • Anti-CD22 CAR T product: 5.3 ± 2.4 ×106/kg
  • Treatment occurred between March 2016 and January 2018
  • Patients were followed-up until death, lost to follow-up, or withdrawal of consent
Efficacy5

Reported here only in patients with NHL. To read the results in ALL, please refer to the original paper.

In patients with NHL who were evaluable for efficacy (n= 36), with a minimum follow-up of three months, 18 patients had achieved complete responses (CR), with eight more achieving a partial response (PR), giving an overall response rate (ORR) of 72.2% (Table 1). The ORR was consistent across subgroups when analyzed by pathologic subtype or cytogenetic risk.

Table 1. Efficacy of CAR T infusions in patients with B-cell NHL, and sub-analysis in patients with diffuse large B-cell lymphoma (DLBCL)

 

Patients with B-cell NHL

(n= 36)

95% CI

Patients with DLBCL

(n=23)

95% CI

ORR

72.2%

54.8–85.8

-

-

CR

50.0%

32.9–67.1

-

-

PR

22.2%

10.1–39.2

-

-

Median progression-free survival (PFS)*

9.9 months

3.3–not reached (NR)

5.8 months

3.0–NR

Twelve-month PFS

50.0%

33.4–64.5

47.8%

26.8–66.1

Median overall survival (OS)*

18.0 months

6.1–NR

18.0 months

5.2–NR

Twelve-month OS

55.3%

38.3–69.3

-

-

* Median follow-up of 14.4 months (range 0.4–27.4) in patients with B-cell NHL, and 14.3 months (0.4–27.3) in patients with DLBCL

Responses:

  • Ongoing responses, at data cut-off (31st March 2019):
    • CR: 15/18 maintained response
    • PR: 3/8 maintained response
    • Eleven patients subsequently underwent SCT (nine autologous and two allogeneic)
      • Six maintained initial CR without PD
  • In patients who did not respond at three months:
    • Median progression-free survival (PFS): 2.4 months (95% CI, 1.0–2.7)
    • Median overall survival (OS): 5.1 months (95% CI, 1.9–6.1)

Analysis by disease status, response at three months, and cytogenetics:

  • Patients receiving CAR T infusions at first relapse had superior survival to those with primary refractory disease or multiple relapses
  • Patients who achieved an ORR at month three (R3M) had a significantly prolonged PFS (p<0.0001) and OS (p<0.0001) compared to others
  • Prognostic impact of genetic abnormalities:
    • Patients with MYC rearrangements (including those with MYC and BCL2 or BCL6), median PFS and OS were NR
    • Of patients with del(17p) or TP53 mutation, median PFS was 8.8 months (95% CI, 1.0–NR) and median OS was 14.5 months (95% CI, 2.7–NR)

Disease progression:

  • PD eventually occurred in 50.0% of patients (n=18)
  • Median time to progression (TTP): 3.3 months (range: 1.0–14.8)
  • At the time of progression, CD19 and/or CD22 CAR T cells were detected in two patients, with B-cell aplasia in three
  • However, repeated biopsy and immunophenotyping did not reveal loss of CD19 or CD22
Safety5

For total cohort (patients with B-ALL and B-cell NHL)

  • Cytokine release syndrome (CRS; graded as per Lee criteria6), any grade: 95.5% (n=85)
    • Grade 1–2 CRS: 77.6%
    • All incidences of grade ≥ 3 CRS and neurotoxicity were reversible aside from one
      • Grade 5 event in patient with B-ALL
    • High-grade (grade ≥ 3) CRS was significantly associated with:
      • Higher levels of serum interleukein-6 (IL-6) in B-ALL and B-cell NHL
      • Higher percentages of bone marrow blasts in B-ALL
      • Increased levels of serum C-reactive protein in B-cell NHL
      • Higher international prognostic index scores in B-cell NHL
    • High-grade (grade ≥ 3) CRS was not significantly associated with:
      • Disease stage
      • CAR T dosage
    • CAR T-cell-related encephalopathy syndrome (CRES): 12 patients (13.5%; all reversible)
  • Most common ≥ grade 3 adverse events (AEs) during the first month: cytopenias
    • The most common grade 3 or higher AEs occurring in more than 5% of patients are shown in Table 2
  • Fatal AEs within the first month: 3 patients
    • One patient died of grade 5 CRS and pneumonia despite the administration of tocilizumab, glucocorticoid and plasma exchange
    • Two patients died of serious pneumonia following infection with cytomegalovirus or stenotrophomonas maltophilia
  • Fatal AEs after the first month: 9 patients
    • Cause of death was infection in five of these patients

Table 2. AEs grade ≥ 3 occurring in ≥ 5% of patients within the first month of infusion

N=89

Grade 3, %

Grade 4, %

Grade 5, %

Lymphocytopenia

0

100

0

Neutrocytopenia

2

98

0

Leukopenia

7

92

0

Anemia

72

10

0

CRS

17

3

1

Fever

36

0

0

Thrombocytopenia

11

52

0

Hypotension

9

0

0

Activated partial thromboplastin time prolonged

6

0

0

Hypokalemia

13

3

0

Diarrhea

6

0

0

Aspartate aminotransferase  increase

7

0

0

Lung infection

18

0

3

Conclusion

The sequential infusion of two separate CAR T products, each targeting a different B-cell antigen, has shown robust responses with a reduction in antigen escape in patients with R/R B-ALL and B-cell NHL.

In patients with B-cell NHL, the survival advantage was most apparent in patients who achieved an overall response at three months, indicating R3M may be a good predictor of survival in this population. This approach was also most beneficial at first relapse, indicating a potential role as second line treatment for patients with R/R B-cell NHL.

However, superior long-term survival was not observed following this dual-targeted approach, with comparable efficacy to single-specific CAR T-cells. The authors suggest efforts are focused on sustaining CAR T persistence in vivo to enable CAR T to become definitive, as opposed to bridging, therapy.

References
  1. FDA. Kymriah (tisagenlecleucel). https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel [Accessed 2019 Nov 07]
  2. FDA. FDA approves axicabtagene ciloleucel for large B-cell lymphoma.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-large-b-cell-lymphoma [Accessed 2019 Nov 07]
  3. EMA. Kymriah. https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah. [Accessed 2019 Nov 07]
  4. EMA. Yescarta. https://www.ema.europa.eu/en/medicines/human/EPAR/yescarta. [Accessed 2019 Nov 07]
  5. Wang N. et al., Efficacy and Safety of CAR19/22 T-cell "Cocktail" Therapy in Patients with Refractory/ Relapsed B-Cell Malignancies. Blood. 2019 Oct 29. DOI: 10.1182/blood.2019000017
  6. Lee DW. et al., Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95. DOI: 10.1182/blood-2014-05-552729
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