Vispa-cel, an allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knockout, in patients with relapsed/ refractory B cell non-Hodgkin lymphoma: Long-term follow-up results from the ANTLER phase 1 trial

Background

Most 2L LBCL patients do not receive treatment with curative intent

• 75% of 2L LBCL patients do not receive autologous CAR-T cell therapies
• No time to wait due to rapid disease progression or CAR-T manufacturing failure
• Geographic, financial, socioeconomic, or insurance issues impact CAR-T accessibility
• Alternative therapies require continuous treatment without curative potential

Vispacabtagene regedleucel (vispa-cel): an allogeneic anti-CD19 CAR-T cell therapy for 2L LBCL 

• Vispa-cel manufactured from healthy donor T cells with 4-1BB costimulatory domain
• PD-1 knockout enhances T cell fitness and antitumor activity
• Anti-CD19 CAR insertion
• TCR knockout

Optimized vispa-cel includes

• Young donor age (<30 years old)
• HLA matched to ≥2 alleles

Single infusion of optimized vispa-cel demonstrates efficacy, safety, and durability on par with auto CAR-Ts

Potential to address unmet need in rapidly progressing, difficult-to-treat, 2L LBCL patients

Methods

85 patients dosed with vispa-cel in ANTLER trial

Eligibility

• Dose escalation: third- or later-line 
  or primary refractory aggressive r/r B-NHL^a
• Dose expansion: second-line LBCL^b (primary refractory disease or relapse ≤12 months after first-line therapy)

Exclusion

• Prior CD19-targeted therapy for 
  CD19-naïve cohorts

Vispa-cel dose levels evaluated

• 40, 80, and 120x10⁶ CAR-T cells
• 80x10⁶ CAR-T cells determined as RP2D

ANTLER trial design for all cohorts

Lymphodepletion: Cyclophosphamide (60 mg/kg/d for 2 days) followed by fludarabine (25 mg/m²/d for 5 days)

Rapidly progressing disease, patients unwilling to go through apheresis or bridging therapy, insurance rejection, or preference for an off-the-shelf therapy are key reasons why investigators enrolled patients in ANTLER trial (NCT04637763)

B-NHL subtypes include: DLBCL, HGBL, tFL, PMBCL, FL [follicular lymphoma, with POD24 (high risk)], MCL, and MZL 

LBCL subtypes include: DLBCL NOS, HGBL, transformed DLBCL from FL or MZL, and PMBCL

Based on survey answers from ANTLER investigators asking why patients were dosed with vispa-cel versus autologous CAR-T cell therapy; 86% of ANTLER sites offer one or more of the approved auto CAR-Ts in 2L LBCL

Patient population

Total treated

• R/R B-NHL 40M, 80M, 120M CAR-T cells

Optimized vispa-cel

• 2L and 3L+ LBCL
• 40M, 80M, 120M CAR-T cells
• Young donor (<30 yo)
• 2+ HLA matching

Pivotal optimized vispa-cel

• 2L LBCL
• 80M CAR-T cells
• Young donor (<30 yo)
• 2+ HLA matching
• This subgroup best represents the treatment regimen and patient population for the planned pivotal trial

Baseline characteristics

2L (N=32) and 3L+ (N=3) LBCL patients treated with 40M, 80M, or 120M vispa-cel CAR-T cells optimized for multiple factors, including 2+ HLA matched and young donor

2L LBCL patients treated with 80M vispa-cel CAR-T cells optimized for multiple factors, including 2+ HLA matched and young donor  

ECOG of 0 or 1 eligible for ANTLER trial

Includes patients with no CR to 1L therapy or CR with duration from end of therapy to PD of ≤6 months 

LBCL subgroup only 

Bulky disease defined by maximum baseline lesion diameter ≥7.5 cm

Efficacy

Optimized vispa-cel delivered durable, long-term efficacy

2L (N=32) and 3L+ (N=3) LBCL 2+ HLA matched, dosed with vispa-cel from young donors (40M, 80M, or 120M doses)

2L (N=27) LBCL patients treated with 80M vispa-cel CAR-T cells optimized for multiple factors, including 2+ HLA matched and young donor 

Median follow-up for PFS is 16.1 mo for optimized vispa-cel (all patients), and 15.1 mo for pivotal optimized vispa-cel 

Median follow-up for DoR is 14.2 mo for optimized vispa-cel (all patients), and 11.2 mo for pivotal optimized vispa-cel

Single 80M dose of pivotal optimized vispa-cel in 2L LBCL patients drives long-term, potentially curative responses

2L LBCL patients treated with 80M vispa-cel CAR-T cells optimized for multiple factors, including 2+ HLA matched and young donor 

Long-term follow-up data reflect the last known response; marked timepoints indicate confirmation of no disease progression

Two grade 5 AEs occurred: IEC-HS (day 25 post-infusion; related to vispa-cel) and PML (day 520 post-infusion; possibly related to vispa-cel.

Certain patients converted from CR or PR to PD at various assessments time points as indicated in the chart above

Safety and tolerability

Generally well-tolerated safety profile enables outpatient administration and further expansion to community sites

Six grade 5 AEs: 2 related, 1 possibly related, 3 unrelated (bladder perforation secondary to BK virus [related]; IEC-HS [related]; PML [possibly related]; acute respiratory failure [unrelated]; acute respiratory distress syndrome [unrelated]; HHV6 encephalitis [unrelated]

2L (N=32) and 3L+ (N=3) LBCL patients treated with 40M, 80M, or 120M vispa-cel CAR-T cells optimized for multiple factors, including 2+ HLA matched and young donor 

2L LBCL patients treated with 80M vispa-cel CAR-T cells optimized for multiple factors, including 2+HLA matched and young donor 

For vispa-cel, prolonged cytopenias are defined as Grade 3 or 4 neutropenia, thrombocytopenia, or anemia ongoing at day 30 (+/- 5 days) post CAR-T infusion, based on laboratory data, distinct from investigator-reported clinical adverse events. Analysis includes patients with assessments at day 30 (+/-5 days). 

Translational analyses

CAR-T cell expansion and functional persistence correlate with duration of response and HLA match level 

Average of log transformed values shown; error bars represent standard error;  ^aProgression <3 mo N=14; response ongoing ≥3 months N=21; ^bHLA match <2 N=9, HLA match ≥2 N=45
Response categories determined at Month 3/Week 12 visit; visits with <50% subject data available are excluded; repeat assay results for the same subject sample were excluded (n=1 and n=3, respectively). 

Rapid hematologic and immunologic recovery after vispa-cel contributes to generally well-tolerated safety profile 

B cell, T cell, and cell depletion and recovery to baseline levels in optimized cohort

Absolute neutrophil and platelet count recovery to Grade ≤2

95% of neutropenia and 88% of thrombocytopenia cases recover by 60 days

Optimized cohort N=35; average of log transformed values shown with ribbons reflecting standard error; Baseline B cells absolute levels calculated with data points ≥ LLOQ;LD: lymphodepletion; LLOQ: lower limit of quantification 

Next Steps

LBCL subtypes include DLBCL NOS, HGBL (with MYC and BCL2 and/or BCL6), HGBL NOS, transformed DLBCL from FL or MZL, FL3B, PMBCL

Enrollment to include patients who are ineligible for transplant and not a candidate or ineligible for auto CAR-T cell therapy based on access challenges or medical criteria, including the need for urgent therapy

Patients in the comparator arm to be treated with an investigator’s choice of SOC regimens: R-GemOx (rituximab+gemcitabine+ oxaliplatin); Pola-RGO (polatuzumab vedotin+rituxumab+gemcitabine+oxaliplatin); or tafasitamab+lenalidomide. 

Single infusion of vispa-cel following a lymphodepletion regimen of cyclophosphamide 60 mg/kg/d x 2d and fludarabine 25 mg/m²/d x 5d

Will only be performed after study is fully enrolled

Conclusions

• Vispa-cel is a allogeneic CAR-T cell therapy
  • PD-1 knockout potentially contributes to enhanced antitumor activity
  • Donor age and partial HLA matching improve clinical outcomes
  • Long-term durable remissions demonstrated after a single infusion of optimized vispa-cel in 2L LBCL patients, most with rapidly progressing disease; 82% ORR, 67% CR rate, and 17.1 mo median PFS
  • Generally well-tolerated safety profile enables outpatient administration and use in the community setting
  • Rapid hematologic and immunologic recovery, unique to vispa-cel, contributes to the generally well-tolerated safety profile