The Emerging Role of CAR T Cell Therapy in Relapsed/Refractory Hodgkin Lymphoma

Abstract

Treatment for Hodgkin lymphoma (HL) has evolved considerably from the time it was originally described in the 19th century with many patients now being cured with frontline therapy. Despite these advances, upwards of 10% of patients experience progressive disease after initial therapy with an even higher percentage relapsing. Until recently there had been limited therapeutic options for relapsed and/or refractory HL outside of highly intensive chemotherapy with stem cell rescue. Improved understanding of the pathophysiology of HL, coupled with the emergence of more targeted therapeutics, has reshaped how we view the treatment of relapsed/refractory HL and its prognosis. With this, there has been an increased focus on immunotherapies that can reprogram the immune system to better overcome the immunosuppressive milieu found in HL for improved cancer cell killing. In particular, chimeric antigen receptor (CAR) T cells are emerging as a valuable therapeutic tool in this area. Building on the success of antibody-drug conjugates directed against CD30, CAR T cells engineered to recognize the same antigen are now reaching patients. Though still in its infancy, CAR T therapy for relapsed/refractory HL has shown exceptional promise in early-stage clinical trials with the potential for durable responses even in patients who had progressed through multiple lines of prior therapy. Here we will review currently available data on the use of CAR T cells in HL, strategies to optimize their effectiveness, and how this therapy may fit into the treatment paradigm of HL going forward.

Keywords: CAR T cells; CD30; immunotherapy; relapsed/refractory Hodgkin lymphoma.

Figure 1

Novel CAR T approaches in HL: Emerging strategies for optimizing CAR T therapy include the following: (1) Modulation of the Immunosuppressive TME—the hallmark of classical Hodgkin lymphoma is relatively few malignant Hodgkin Reed–Sternberg (HRS) cells interspersed in an immune infiltrate dominated by immunosuppressive cells, including regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells, among others. As these immune cells represent the bulk of the tumor, therapies targeting the TME could improve treatment response in cases of relapsed and/or refractory HL. To date, this has included CAR T products targeting TAMs (anti-CD123), as well as regulatory B-cells (anti-CD19), in the TME. The PD-1/PD-L1/L2 axis represents a critical mechanism that leads to CAR T dysfunction and combined use of checkpoint inhibitors may allow for a more prolonged anti-tumor effect. (2) Increased CAR T cell Persistence—Ongoing tumor control requires that CAR T cells be successfully recruited to the TME in order to carry out their function. HRS cells are known to secrete high levels of CCL17, which is generally used to recruit immunosuppressive cells. CAR T cells engineered to express the receptor to CCL17 (CCR4) may allow for increased penetration of CAR T cells into the TME, leading to enhanced antitumor activity. Memory T cells have been shown to persist longer than traditional effector cells and strategies to enhance their formation, including the cytokine milieu (i.e., IL-7 and IL-15) that is used for their ex vivo expansion, may impact the number of infused memory cells. (3) Novel antigens—Natural killer (NK) cells are emerging as an alternative to traditional T cells for the introduction of the chimeric antigen receptor. Supporting the efficacy of NK cells for this purpose, studies have demonstrated that a CD16/CD30 bispecific antibody that re-engages NK cells to target HRS cells can lead to tumor regression in relapsed/refractory HL patients. While HRS cells do not appear to experience antigen loss as a mechanism of CAR T cell resistance as of yet, novel targets may allow for the development of other CAR T cells or even multiantigen targeted CAR T cells to improve responses in patients. Similar to this idea, cytotoxic T cells expanded ex vivo to recognize tumor-associated antigens, such as WT1, PRAME, or Survivin, have shown promise in treating HL. Figure created with Biorender.com.