CAR-20/19-T Cells

P1, N=24, Suspended, Medical College of Wisconsin | Recruiting --> Suspended

P1/2, N=100, Recruiting, Medical College of Wisconsin | Trial completion date: Dec 2025 --> Jan 2025 | Trial primary completion date: Dec 2025 --> Jan 2025

P1, N=12, Not yet recruiting, Medical College of Wisconsin | Trial completion date: Feb 2025 --> Jul 2027 | Initiation date: Apr 2024 --> Jul 2024 | Trial primary completion date: Nov 2024 --> Jul 2026

Cryopreservation of LV20.19 CAR T-cell therapy had no meaningful impact on ORR, DOR, toxicity profile, time to CRS, or in-vivo expansion. Although fresh products facilitate shorter time from apheresis to infusion, cryopreservation may allow for rapid advancement of products to multicenter trials and licensure.

12 pts (86%) had disease progression on covalent BTKi and venetoclax...In terms of safety, 100% (n=14) developed CRS and 93% (n=13) required tocilizumab...Six (66%) IEC-HS pts required anakinra for management... While LV20.19 CAR T cells were efficacious in CLL and RT it was limited by high rates of IEC-HS especially among CLL pts, a phenomena not commonly seen with other histologies. With two DLTs in the CLL cohort, the dose for future CLL pts was reduced to 1x10e6 cells/kg. Additional studies are needed to understand how CLL biology drives CAR IEC-HS.

P1, N=12, Not yet recruiting, Medical College of Wisconsin | Initiation date: Oct 2023 --> Feb 2024

Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts...Both received only a single dose of intrathecal hydrocortisone (no systemic steroids) with resolution of neurotoxicity within 24 hours of administration... Bispecific LV20.19 CAR T-cells with adaptive MF process is feasible, safe, and efficacious for R/R MCL with ORR 100%, no Grade 3+ CRS and low rates of Grade 3+ ICANS (12%). Adaptive MF enriched the final product with higher percentages of T-SCM/T-CM CAR cells and allowed most pts to receive CAR-T cells within 8 days of apheresis. Dual targeting of CD20 and CD19 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL.

P1, N=24, Recruiting, Medical College of Wisconsin | Trial completion date: Feb 2024 --> Jun 2026 | Trial primary completion date: Oct 2023 --> Jun 2025

P1/2, N=100, Recruiting, Medical College of Wisconsin | N=65 --> 100 | Trial primary completion date: Dec 2023 --> Dec 2025

After safety run-in, we opened a 14-patient single stage Phase II MCL arm with flexible 8/12-day manufacturing (MF) and goal of fresh infusion with a target complete response (CR) rate of 50% to exceed the historical CR rate of Ibrutinib in R/R MCL of 20%...Eleven of 14 pts (79%) progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 5 (36%) of these pts also progressed on a non-covalent BTKi (pirtobrutinib) administered on a clinical trial...Bispecific LV20.19 CAR T-cells expanded with IL7/IL15 and manufactured onsite are safe and efficacious for R/R MCL with a day 90 ORR of 100%, and only one relapse to date with a median follow-up of nearly 2-years. Toxicity profile was encouraging with no Grade 3+ CRS and low rates of Grade 3+ ICANS. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with R/R MCL.

At time of RT diagnosis, all patients received R-CHOP chemotherapy as frontline management. Bispecific LV20.19 CAR T-cell therapy resulted in robust early and durable responses in patients with heavily pre-treated CLL and RT. To date, there is limited data on outcomes for RT with CAR T-cell therapy. Given historical outcomes, bispecific LV20.19 CAR T cells offer a promising strategy for R/R RT.

Nine of 11 pts had progressed on a Bruton’s Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had also progressed on a non-covalent BTKi (pirtobrutinib) administered on a clinical trial (Table 1). Bispecific LV20.19 CAR T-cells expanded with IL7/IL15 are safe and efficacious for R/R MCL with an ORR of 100%, no relapses with a median follow-up of >1.5 years, no Grade 3+ CRS, and low rates of Grade 3+ ICANS (9%). All pts on the Phase II arm had CAR T-cells manufactured on-site in 8 days with fresh CAR T-cell infusion and lymphodepletion starting during MF. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with R/R MCL.

There were 15 patients in the IL-2 trial and 22 patients in the IL-7+15 trial with adequate LV20.19 CAR T-cells for analysis. For cells expanded in IL-7+15 vs IL-2, the global PFA was 53.14% vs 40.12%, p=0.01, CD8 PFA was 51.15% vs 41.24% p=0.01, while the CD4 PFA was 55.05% vs 46.23%, p=0.08, (Figure 1A). Similarly, the global PSI was 1508 vs 956 p=0.0003, CD8 PSI was 1333 vs 865 p=0.0009, and CD4 PSI was 1580 vs 865, p<0.0001.

Bridging therapy and higher absolute lymphocyte count on day of CAR-T infusion were associated with inferior survival outcomes. In conclusion, this initial trial of LV20.19 CAR-T demonstrates a signal for favorable long-term outcomes for patients with R/R B-cell malignancies.

Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R MCL with ORR 100%, no relapses with a median follow-up of >1.5 years, and no Grade 3+ CRS and low rates of Grade 3+ ICANS (10%). All pts on the Phase II arm had CAR T-cells manufactured on-site utilizing an 8-day platform with fresh CAR T-cell infusion and lymphodepletion starting during manufacturing. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL.

Bispecific LV20.19 CAR T-cells are safe and efficacious for pts with R/R B-cell NHL. Shorter MF produced a more naïve CAR T-cell product with no difference in toxicity profile. Higher percentage of CM T-cells and lower EMRA T-cells were observed earlier in the MF process both between the two cohorts and intra-patient.

Relapse after CAR T-cell therapy remains a significant clinical challenge. New predictors are indicated to determine which responding patients after CAR-T cell therapy are more likely to relapse. Utilizing the commercially available Adaptive clonoSEQ® assay, early MRD assessment was not predictive of long-term clinical outcomes in DLBCL and FL.

P1, N=26, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed | Trial completion date: Oct 2022 --> Aug 2021

P1/2, N=65, Recruiting, Medical College of Wisconsin | N=32 --> 65 | Trial completion date: May 2025 --> Dec 2025 | Trial primary completion date: May 2023 --> Dec 2023

P1, N=24, Recruiting, Medical College of Wisconsin | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Oct 2022 --> Oct 2023

Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R B-cell NHL with a high ORR and low rates of grade ≥3 CRS or ICANS. Early results demonstrate immunophenotypic differences and improved responses among pts treated with a shorter 8-day MF process.

Earlier CRS onset and increased pain were also seen in low SES patients, with qualitatively higher incidences of CRS, neurotoxicity, and poor sleep. Future work will focus on acquiring a larger sample to further delineate the impact of SES on cancer outcome disparities among CAR T-cell recipients, including but not limited to PROs, neurotoxicity, and survival.

Given the composition of CAR-T products has been shown to impact anti-tumor efficacy, this suggests that manufacturing bispecific CAR T-cells in IL7+15 for a shorter duration could lead to greater clinical efficacy without negatively impacting attainment of cell dose. Clinical outcomes of 8- vs 12-day manufactured IL-7+15 expanded LV20.19 CAR T-cells will be reported separately.

Expansion of LV20.19 CAR T-cells in IL7+15 may generate a more robust CAR-T product than expansion in IL-2, which could improve persistence, cytotoxicity, and ultimately patient outcomes. An ongoing prospective trial (NCT04186520) is evaluating clinical outcomes with IL-7+15 expanded LV20.19 CAR T-cells and is reported separately.

Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R B-cell NHL with a high ORR and low rates of grade ≥3 CRS or ICANS. Early results demonstrate immunophenotypic differences and improved responses among pts treated with a shorter 8-day MF process. MCL outcomes were impressive with a 100% ORR and no relapses to date.

P1, N=24, Recruiting, Medical College of Wisconsin | Not yet recruiting --> Recruiting