Targeting Immune System Alterations in Hodgkin Lymphoma

Purpose of Review: This review discusses novel immunotherapeutic approaches to treat Hodgkin lymphoma (HL), specifically PD-1 inhibitors and cellular immunotherapy. Recent Findings: PD-1 inhibitors have shown promising results in the treatment of relapsed or refractory HL, leading to FDA approval of nivolumab and pembrolizumab, although complete remissions are rare. Chimeric antigen receptor T cells directed against CD30 have been investigated with preliminary clinical trials showing minimal toxicities and some responses in heavily pre-treated patients with HL. Summary: HL is unique as it consists of a small percentage of malignant cells (Hodgkin Reed Sternberg cells) surrounded by an inflammatory microenvironment which promotes tumor growth and suppresses immune responses, making it an ideal target for immunotherapeutic approaches, such as PD-1 inhibitors and cellular immunotherapy. Current research is focused on overcoming barriers to efficacy via rational combinations that overcome resistance to therapy

Challenges of driving CD30-directed CAR-T cells to the clinic

Chimeric antigen receptor T (CAR-T) cells are a promising new treatment for patients with relapsed or refractory hematologic malignancies, including lymphoma. Given the success of CAR-T cells directed against CD19, new targets are being developed and tested, since not all lymphomas express CD19. CD30 is promising target as it is universally expressed in virtually all classical Hodgkin lymphomas, anaplastic large cell lymphomas, and in a proportion of other lymphoma types, including cutaneous T cell lymphomas and diffuse large B cell lymphomas. Preclinical studies with CD30-directed CAR-T cells support the feasibility of this approach. Recently, two clinical trials of CD30-directed CAR-T cells in relapsed/refractory CD30+ lymphomas, including Hodgkin lymphoma, have been reported with minimal toxicities noted and preliminary efficacy seen in a proportion of patients. However, improving the persistence and expansion of CAR-T cells is key to further enhancing the efficacy of this treatment approach. Future directions include optimizing the lymphodepletion regimen, enhancing migration to the tumor site, and combination with other immune regulators. Several ongoing and upcoming clinical trials of CD30-directed CAR-T cells are expected to further enhance this approach to treat patients with relapsed and refractory CD30+ lymphomas

Extending the Promise of Chimeric Antigen Receptor T-Cell Therapy Beyond Targeting CD19+ Tumors

Chimeric antigen receptor T cells (CAR-Ts) targeted against CD19 have shown impressive activity in patients with B-cell leukemias and lymphomas. This has revolutionized the treatment landscape for patients with relapsed or refractory (r/r) disease, providing hope for a possible curative approach for those who previously had limited available treatment options. The success of this approach has prompted interest in studying CAR-Ts for other hematologic malignancies and the development of CARs specific for other antigens. In this review, we discuss recent developments in CAR-Ts in multiple myeloma (MM), Hodgkin lymphoma (HL), T-cell malignancies, and acute myelogenous leukemia (AML; Fig 1)

Identification of a novel stripe rust resistance gene from the European winter wheat cultivar ‘Acienda’: A step towards rust proofing wheat cultivation

All stage resistance to stripe rust races prevalent in India was investigated in the European winter wheat cultivar ‘Acienda’. In order to dissect the genetic basis of the resistance, a backcross population was developed between ‘Acienda’ and the stripe rust susceptible Indian spring wheat cultivar ‘HD 2967’. Inheritance studies revealed segregation for a dominant resistant gene. High density SNP genotyping was used to map stripe rust resistance and marker regression analysis located stripe rust resistance to the distal end of wheat chromosome 1A. Interval mapping located this region between the SNP markers AX-95162217 and AX-94540853, at a LOD score of 15.83 with a phenotypic contribution of 60%. This major stripe rust resistance locus from ‘Acienda’ has been temporarily designated as Yraci. A candidate gene search in the 2.76 Mb region carrying Yraci on chromosome 1A identified 18 NBS-LRR genes based on wheat RefSeqv1.0 annotations. Our results indicate that as there is no major gene reported in the Yraci chromosome region, it is likely to be a novel stripe rust resistance locus and offers potential for deployment, using the identified markers, to confer all stage stripe rust resistance

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma

PURPOSE Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies