Anti-CD30 CAR T-cell therapy in patients with heavily pretreated R/R HL

Patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) whose salvage therapy has failed have a poor prognosis. Treatment with chimeric antigen receptor (CAR) T-cell therapy, which has shown effectiveness in B-cell malignancies, could be a valid alternative for HL treatment.

A phase I study, evaluating the safety of anti-CD30 CAR T-cell therapy in patients with HL, reported that the infusion of CD30-targeting CAR T cells (CD30.CAR-Ts) with no previous lymphodepleting chemotherapy was well tolerated, but resulted in only a 33% overall response rate (ORR).¹ Two parallel phase I/II trials have evaluated the efficacy and safety of the autologous CD30.CAR-Ts after lymphodepleting chemotherapy in heavily pretreated patients with R/R HL. The results of these studies were recently published by Carlos Ramos and colleagues in the Journal of Clinical Oncology.²

Study design²

The two parallel phase I/II trials enrolled patients with R/R CD30⁺ HL who relapsed after ≥ 2 lines of therapy. Patients were enrolled at two centers: the University of North Carolina (UNC, NCT02690545; n = 28) and the Baylor College of Medicine (BCM, NCT02917083; n = 28). Bridging chemotherapy was allowed before lymphodepletion. Of the 28 patients enrolled at UNC, 25 were treated. Of the 28 patients enrolled at BCM, 17 were treated, including one patient that was previously treated at UNC.

Treatment schedule

• Lymphodepletion
  • At UNC: Bendamustine (benda) 90mg/m²/day for two days for the first cohort (n = 8), and benda 70 mg/m²/day plus fludarabine (flu) 30 mg/m²/day for 3 days for the second cohort.
  • At BCM: Cyclophosphamide (Cy) 500 mg/m²/day and flu 30 mg/m²/day for 3 days.
• Patients received CD30.CAR-T infusion 2–5 days after lymphodepletion:
  • At BCM, patients received either 2 × 10⁷ CAR T cells/m² (dose level [DL] 1), 1 × 10⁸ CAR T cells/m² (DL2), or 2 × 10⁸ CAR T cells/m² (DL3).
  • At UNC, patients received 1 × 10⁸ CAR T cells/m² (DL 2) or 2 × 10⁸ CAR T cells/m² (DL3).
• In patients with stable disease (SD) or partial response (PR) after the first treatment, a second infusion was allowed.

The treatment scheme is reported in Figure 1.

BCM, Baylor College of Medicine; benda, bendamustine; Cy, cyclophosphamide; DL, dose level; flu, fludarabine; UNC, University of North Carolina. 

Endpoints

The primary endpoint for both studies was safety. Secondary endpoints were ORR, overall survival (OS), and expansion and persistence of CD30.CAR-Ts in the peripheral blood after infusion.

Results²

Patient characteristics

Baseline patient characteristics are reported in Table 1.

Table 1. Baseline patient characteristics²

allo-SCT, allogeneic stem cell transplantation; auto-SCT, autologous stem cell transplantation; benda, bendamustine; BV, brentuximab vedotin; CPI, checkpoint inhibitor; Cy, cyclophosphamide; ECOG PS, Eastern Cooperative Oncology Group performance status; flu, fludarabine; HL, Hodgkin lymphoma; MC, mixed cellularity; NOS, not otherwise specified; NS, nodular sclerosis. *Both treatments are included for the patient who was treated twice.
Characteristic	All patients (N = 42)*	Benda (n = 8)*	Benda-flu (n = 17)	Cy-flu (n = 17)*
Median age, years (range)	35 (17─69)	49 (23─67)	32 (23─45)	36 (17─69)
HL subtype, n (%)
NS	32 (76)	6 (75)	10 (59)	16 (94)
MC	4 (10)	2 (25)	2 (12)	0 (0)
NOS	6 (14)	0 (0)	5 (29)	1 (6)
Stage at disease, n (%)
I─II	14 (33)	1 (13)	7 (41)	6 (35)
III─IV	28 (67)	7 (88)	10 (59)	11 (65)
ECOG PS ≥ 1, n (%)	34 (81)	5 (63)	12 (71)	17 (100)
Median number of prior therapies (range)	7 (2─23)	7.5 (5─17)	8 (3─23)	5 (2─10)
Bridging therapy, n (%)	28 (67)	8 (100)	10 (59)	10 (59)
Prior BV, n (%)	38 (90)	8 (100)	16 (94)	14 (82)
Prior CPI, n (%)	34 (81)	7 (88)	13 (76)	14 (82)
Prior auto-SCT, n (%)	32 (76)	7 (88)	14 (82)	11 (65)
Prior allo-SCT, n (%)	10 (24)	2 (25)	8 (47)	0 (0)

Safety

The treatment was well tolerated, with no dose-limiting toxicities associated with CD30.CAR-T infusions observed. The most common ≥ Grade 3 adverse events are reported in Table 2.

Table 2. Most common Grade 3 or higher adverse events²

Benda, bendamustine; CRS, cytokine release syndrome; Cy, cyclophosphamide; flu, fludarabine. *Both treatments are included for the patient who was treated twice.
Adverse event, n (%)	All patients (N = 42)*	Benda (n = 8)*	Benda-flu (n = 17)	Cy-flu (n = 17)*
Lymphopenia	42 (100)	8 (100)	17 (100)	17 (100)
Leukopenia	24 (57)	3 (38)	8 (47)	13 (76)
Rash (any grade)	20 (48)	2 (25)	4 (24)	14 (82)
Neutropenia	20 (48)	2 (25)	7 (41)	11 (65)
Thrombocytopenia	11 (26)	1 (13)	7 (41)	3 (18)
Grade 3–4 thrombocytopenia not resolved by Day 28	10 (24)	0 (0)	7 (41)	3 (18)
CRS (all Grade 1)	10 (24)	1 (13)	2 (12)	7 (41)

In total, cytokine release syndrome (CRS) was observed in 24% of patients, all of which were Grade 1 with a median onset of 10 days (range, 7─24) and a median duration of 4 days (range, 1─6). All the CRS events resolved spontaneously without the need for tocilizumab or corticosteroids.

Neurologic toxicity was not observed.

Efficacy

Clinical responses were evaluated in 37 patients with measurable disease at the time of treatment, and rates are reported in Table 3. In patients who received flu-based lymphodepletion, the ORR was 72% (n = 32), with 59% of patients (n = 19) achieving a complete response (CR).

Table 3. Clinical responses²

Benda, bendamustine; CR, complete response; Cy, cyclophosphamide; flu, fludarabine; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Response	All patients (n = 37)	Benda (n = 5)	Benda-flu (n = 15)	Cy-flu (n = 17)
ORR, n (%)
CR + PR	23 (62)	0 (0)	12 (80)	11 (65)
Response rate, n (%)
CR	19 (51)	0 (0)	11 (73)	8 (47)
PR	4 (11)	0 (0)	1 (7)	3 (18)
SD	4 (11)	1 (20)	1 (7)	2 (11)
PD	10 (27)	4 (80)	2 (13)	4 (24)

After a median follow-up of 533 days:

• 1-year progression-free survival (PFS) in 37 evaluable patients was 36% (95% CI, 21─51), with longer PFS in patients receiving a flu-based conditioning than in patients receiving benda alone (p = 0.0002).
• Median PFS for the 19 patients who achieved CR was 444 days.
• 1-year OS for all 41 patients (counting the one patient treated at both sites only once) was 94% (95% CI, 79─99).

CAR-T cell expansion and persistence

In patients receiving flu-based lymphodepletion, the peak of CD30.CAR-T expansion was observed in the first 2─3 weeks after infusion.

CD30.CAR-Ts persistence was cell-dose dependent, with a higher persistence in patients receiving 2 × 10⁸ CAR-Ts/m² than in patients receiving 2 × 10⁷ CAR-Ts/m² or 1 × 10⁸ CAR-Ts/m² (p < 0.001), irrespective of the lymphodepleting regimen used.

Conclusion

In a heavily pre-treated population of patients with R/R HL, the infusion of autologous CD30.CAR-Ts after flu-based lymphodepletion was well tolerated, with a high rate of durable responses. These promising results highlight the feasibility of CAR T-cell therapies in HL, providing a potential new therapeutic option that could be further investigated for its use in both later and earlier stages of the disease.