P1, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center

P1, N=18, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center

Matched clones were present at low magnitude in the infused CD30.CAR-T product for all CH cases but did not affect the product's immunophenotype or transduction efficiency. As cellular immunotherapies expand to become frontline treatments for hematological malignancies, our data indicates CAR-T recipients could be enriched for CH, and further longitudinal studies centered on CH complications in this population are warranted.

P1, N=90, Not yet recruiting, Baylor College of Medicine

There has been much research into CD30 CAR-T cells as a result of their successful use in treatment of r/rHL. This research has helped us to understand CD30 CAR-T-cell safety as well as the management options available before and after its administration to increase patient survival and reduce side effects.

P1, N=0, Withdrawn, Baylor College of Medicine | N=18 --> 0 | Not yet recruiting --> Withdrawn

CD30 CAR-T cell therapy has a favorable toxicity profile with patient physical function and symptom burden recovering to at least their baseline pretreatment health by 1 month post infusion. Trial registration number: NCT02690545.

P1/2, N=40, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial completion date: Aug 2038 --> Aug 2040 | Trial primary completion date: Aug 2023 --> Aug 2025

Hence, our findings document that certain levels of CD30 expression are retained by the neoplastic cells. This is not only of biological interest but also diagnostically important, as detection of CD30 is an essential factor in establishing a diagnosis of CHL.

Two patients had cytokine release syndrome (Grade 1), which resolved without use of steroid or tocilizumab. Preliminary data demonstrated favorable safety profile and promising anti-tumor responses of CD30.CAR-T combined with nivo in r/r cHL patients after failure of frontline therapy. Evaluation of 15 patients enrolled is ongoing, and the clinical and ctDNA-MRD data will be presented at the meeting.

P1, N=21, Active, not recruiting, Tessa Therapeutics | Trial primary completion date: Mar 2023 --> Nov 2022

P1b, N=15, Active, not recruiting, Tessa Therapeutics | Recruiting --> Active, not recruiting

P1, N=18, Not yet recruiting, Baylor College of Medicine | Trial completion date: Jun 2038 --> Jun 2040 | Trial primary completion date: Jun 2023 --> Jun 2025

P1, N=0, Withdrawn, UNC Lineberger Comprehensive Cancer Center | N=10 --> 0 | Trial completion date: Dec 2030 --> May 2022 | Active, not recruiting --> Withdrawn

P1, N=60, Recruiting, Baylor College of Medicine | Trial completion date: Feb 2036 --> Feb 2040

P2, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Aug 2023 --> Feb 2028

P1, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Jul 2023 --> Apr 2024

Preliminary results from the proposed strategy suggest that a self-replicating and constitutive biological treatment that continuously target the PD1/PDL1 immunosuppressive pathway could be a new strategy to boost immune attack in the immunosuppressive tumor microenvironment, matching T cell activity and PD-1/PD-L1 blockade at the time. Further investigations are required to confirm early findings and explore if this approach could also enhance T cell persistence in vivo through the 4.1BB stimulation triggered by PDL1+ cells.

P2, N=18, Recruiting, UNC Lineberger Comprehensive Cancer Center | Not yet recruiting --> Recruiting

The recurrence of DNMT3A and PPM1D mutations indicates the selective influence of prior chemotherapeutics. Given the increasing number of patients receiving CAR-T therapy, further work must determine if high CH prevalence in this cohort is predictive of increased long-term complications in survivors.

P2, N=18, Not yet recruiting, UNC Lineberger Comprehensive Cancer Center

The efficacy and safety profile of programmed death (PD)-1 checkpoint inhibitors, nivolumab and pembrolizumab, in cHL have been well demonstrated (Chen et al., 2017; Kuruvilla et al., 2021; Younes et al., 2016), with FDA approval for r/r cHL. PD-1 checkpoint inhibitors, in combination with CD30-directed antibody therapy (brentuximab vedotin) or other chemotherapies, have also shown high efficacy in this setting (Advani et al., 2021; Mei et al., 2022; Moskowitz et al., 2021)...Following a leukapheresis procedure for manufacture of CD30.CAR-T cells, patients will be treated with 4 cycles of nivolumab every 4 weeks (Q4W), and a single infusion of CD30.CAR-T cells (given between nivolumab Cycles 2 and 3, and after lymphodepletion with bendamustine and fludarabine)...The key secondary objective is to evaluate potential anti-tumor activity, as assessed by the CR rate of autologous CD30.CAR-T in combination with nivolumab at EOT in 14 evaluable patients, as per Lugano Classification Revised Response System for malignant lymphoma (Cheson et al., 2014). Other secondary objectives are to assess the overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) of patients in the ASCT and non-ASCT groups.This study is ongoing and one patient has been enrolled to date.

The anti-PD-1 antibodies nivolumab and pembrolizumab have both been studied in phase II studies in patients with r/r cHL with ORR ranging between 65-87% and median progression free survival (PFS) ranging from 13-15 months...This study is the first to describe CD30.CAR-T expansion following anti-PD-1 therapy. While further analysis is warranted to assess for CD30.CAR-T functionality after anti-PD-1 exposure, our data suggest that anti-PD-1 therapy may rescue CD30.CAR T cells, supporting further investigations in patients with cHL.

A single infusion of CD30.CAR-T therapy rapidly induces MRD negativity in a significant subset of patients at Day 42. ctDNA as exploratory biomarker will be further evaluated in Pivotal part of the study.

Methods This is a Phase 2 single arm, multi-center study, enrolling patients (12-75 years) with cHL progression after at least 3 lines of therapy, including chemotherapy, brentuximab vedotin, and anti-programmed cell death (PD)-1 antibodies...The patients were treated with CD30.CAR-T cells, after lymphodepletion chemotherapy using bendamustine and fludarabine, with an allowable dose range of 2.0 to 2.7 × 108 CD30.CAR-T cells per m2...The CD30.CAR-T cells showed good expansion and persistence after infusion. The efficacy, safety and exploratory biomarkers of CD30.CAR-T will be further evaluated in the Pivotal segment of this Phase 2 study.

Escalating doses of 4 × 107 (DL1), 1 × 108 (DL2) or 4 × 108 (DL3) CD30.CAR EBVSTs were infused after lymphodepletion with cyclophosphamide and fludarabine. Conclusion We have shown CD30.CAR EBVSTs can be a safe and effective treatment for CD30+ lymphomas, and may avert GVHD and immediate rejection even after multiple infusions. We now seek to improve the durability of responses and test whether CD30.CAR EBVST can be used as a platform for other "off-the-shelf" CAR-T cell therapies.

Our work demonstrates the combined administration of ASCT and CAR30 T-cell therapy is well-tolerate and highly effective in r/r cHL and ALCL, even in PET-positive or chemorefractory patients who are expected to have inferior outcome after ASCT, although further large-scaled validation in prospective clinical trial is warranted. Trial registration The trial was registered with the Chinese Clinical Trial Registry (ChiCTR, number ChiCTR2100053662).

More significantly, CAR-T cells containing CD30-signaling revealed effective cytolytic activities against several solid cancer cell lines based on its scFv fragments. Conclusions Our results demonstrate that the CD30-derived costimulatory domain could be an alternative for developing CAR-engineered therapeutics which may be applicable for various design of CAR constructs, with an emphasis on effectiveness against solid tumors.

Humanized CD30.CARs combined with the 4-1BB-derived spacer did not exhibit any nonspecific interactions with CD16+ immune cells, while displaying superior efficacy in vitro , better persistence in vivo in various humanized mouse models, and more importantly an improved safety profile in a leukemia model with high tumor burden. Conclusions Our re-engineered CD30.CAR construct, consisting of a humanized CD30.CAR and a 4-1BB-derived spacer, is likely to improve allogeneic CD30.CAR EBVST performance.

P1, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Jul 2022 --> Jul 2023

P1, N=18, Recruiting, Baylor College of Medicine | Trial primary completion date: Jun 2022 --> Jun 2025

P1, N=66, Recruiting, Baylor College of Medicine | Trial primary completion date: Apr 2022 --> Apr 2026

P1, N=21, Active, not recruiting, Tessa Therapeutics | Recruiting --> Active, not recruiting

P1b, N=15, Recruiting, Tessa Therapeutics | Not yet recruiting --> Recruiting

P1, N=20, Recruiting, UNC Lineberger Comprehensive Cancer Center | N=10 --> 20

HL patients were R/R to treatments including chemotherapy, brentuximab and anti-PD-1 antibodies, while T-NHL patients were R/R to at least 2 chemotherapy treatments...All patients received LD before infusion, fludarabine/bendamustine in HL patients (n=8) and fludarabine/cyclophosphamide in T-NHL (n=2)...Our Phase 1 study provides evidence for feasibility and safety of HSP-CAR30. Additionally, HSP-CAR30 has shown promising efficacy in heavily treated HL patients that is being explored in a phase 2 trial already started.

To help compare the different systems available, we present three case studies of engineered T cells manufactured for phase I clinical trials at the NIH Clinical Center (CD30 CAR-T cells for lymphoma, CD19/CD22 bispecific CAR-T cells for B cell malignancies, and E7 TCR T cells for human papilloma virus-associated cancers). Continued improvement in cell manufacturing technology will help enable world-wide implementation of engineered T cell therapies.

P1b, N=15, Not yet recruiting, Tessa Therapeutics

Brentuximab vedotin is a humanized anti-CD30 antibody linked to a cytotoxin, and was approved by the US Food and Drug Administration in 2012 for treating refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Since then, the list of Food and Drug Administration-approved CD30-targeted hematologic malignancies has grown. Recently, the therapies using tumor antigen-specific chimeric antigen receptor T cells targeting CD30 have incited a great deal of enthusiasm and are studied in clinical trials.

After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 10/kg and 10/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 10/kg CAR-T cells combined with anti-PD-1 antibody...Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab...Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

P2, N=30, Recruiting, Huazhong University of Science and Technology