Chimeric antigen receptor T-cell therapy targeting CD30 in hodgkin lymphoma

H&O What prompted your research of chimeric antigen receptor (CAR) T-cell therapy in Hodgkin lymphoma? BS It has been known for a long time that Hodgkin lymphoma is susceptible to T-cell immune-mediated treatment. As researchers at Baylor College of Medicine, my colleagues and I evaluated the possibility of using T cells to target the Epstein-Barr virus, which is expressed in approximately 40% of patients with Hodgkin lymphoma. We found that targeting antigens associated with this virus with specific T cells can reduce disease progression and thereby induce complete remissions, which can be sustained in a good number of patients. A drawback to this approach is that only a small subset of patients is eligible for treatment

Adoptive Cell Therapy in Treating Pediatric Solid Tumors

Purpose of Review: This review will discuss the challenges facing adoptive cell techniques in the treatment of solid tumors and examine the therapies that are in development for specifically pediatric solid tumors. Recent Findings: Targeting solid tumors with adoptive cell therapy has been limited by the inhibitory tumor microenvironment and heterogeneous expression of targetable antigens. Many creative strategies to overcome these limitations are being developed but still need to be tested clinically. Early phase clinical trials in neuroblastoma with GD2 CAR T cells are promising but results need to be validated on a larger scale. Most research in other pediatric solid tumors is still in early stages. Summary: Adoptive cell therapy represents a useful tool to improve the outcomes of many pediatric solid tumors but significant study is still required. Several clinical trials are ongoing to test therapies that have shown promise in the lab

lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (c) 2005 by The American Society of Hematology

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

Cancer battlefield: Six characters in search of an author

The great promise of adoptive T-cell therapy for cancer is that of a highly specific and less toxic strategy for killing tumor cells while offering continual and long-term protection against resurgence of tumors. Although theoretically possible, this promise has yet to be achieved in practice. Encouraging results initially came from studies in which tumor-infiltrating T cells were isolated and then expanded and reinvigorated in vitro before being infused back into patients. While promising, this approach, however, requires both access to tumor biopsies, which are not always available, and the ability to expand T cells from the tumor to sufficient numbers for infusion, which is not always possible. Thus, to extend T-cell therapies to more patients, much effort has been put into developing methods for the ex vivo expansion of tumor-specific T cells from peripheral blood, and while successful for virus-associated tumors, the extension to other human malignancies expressing nonviral tumor associated antigens remains challenging due to the low frequency and avidity of tumor-specific T cell receptors (TCRs) on patient-derived T cells. To overcome the inefficient generation of tumor-associated antigen-specific T cells, genetic engineering of lymphocytes with ab‑T‑cell receptor chains, obtained from T cells with high avidity/affinity TCRs, or chimeric antigen receptors, directed against antigens expressed on the surface of tumor cells, have been developed and are now in clinical trials. These efforts have been efficient at providing relatively easy means to broaden the antigen recognition repertoire and to generate large numbers of tumor-specific T cells ex vivo that can then be infused into patients to re-establish the balance between T cells and tumors. However, even the ability to infuse large numbers of tumor-specific T cells has provided limited advancement in the overall fight against tumors

Chimeric antigen receptors (CARs) from bench-to-bedside

Chimeric antigen receptors (CARs) combine the antigen specificity of an antibody with the biologic properties of T lymphocytes. While the concept has been developed more than 20 years ago, only in recent years the clinical application of this approach has produced remarkable objective clinical responses. In this brief review, we outline some specific aspects that have led to antitumor responses in cancer patients

Management of patients with non-Hodgkin’s lymphoma: Focus on adoptive T-cell therapy

Non-Hodgkin’s lymphoma (NHL) represents a heterogeneous group of malignancies with high diversity in terms of biology, clinical responses, and prognosis. Standard therapy regimens produce a 5-year relative survival rate of only 69%, with the critical need to increase the treatment-success rate of this patient population presenting at diagnosis with a median age of 66 years and many comorbidities. The evidence that an impaired immune system favors the development of NHL has opened the stage for new therapeutics, and specifically for the adoptive transfer of ex vivo-expanded antigen-specific T-cells. In this review, we discuss how T-cells specific for viral-associated antigens, nonviral-associated antigens expressed by the tumor, T-cells redirected through the expression of chimeric antigen receptors, and transgenic T-cell receptors against tumor cells have been developed and used in clinical trials for the treatment of patients with NHLs

Adoptive T cell therapy: Boosting the immune system to fight cancer

Cellular therapies have shown increasing promise as a cancer treatment. Encouraging results against hematologic malignancies are paving the way to move into solid tumors. In this review, we will focus on T-cell therapies starting from tumor infiltrating lymphocytes (TILs) to optimized T-cell receptor-modified (TCR) cells and chimeric antigen receptor-modified T cells (CAR-Ts). We will discuss the positive preclinical and clinical findings of these approaches, along with some of the persisting barriers that need to be overcome to improve outcomes

Genetic modification of human T lymphocytes for the treatment of hematologic malignancies

Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virusassociated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies