ONCAlert | Upfront Therapy for mRCC

The Emerging Role of Checkpoint Inhibitors in Lymphoid Malignancies

Shipra Gandhi, MD, Pallawi Torka, MD, and Francisco J. Hernandez Ilizaliturri, MD
Published Online: Feb 25,2016


Checkpoint inhibitors have drawn considerable attention in the field of oncology and hold promise to significantly impact the treatment of lymphomas. The two main targets for immune checkpoint inhibitors in lymphoma are Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 downregulates T-cell activity and leads to a decrease in the antitumor immune response. Hence, blocking CTLA-4 promotes the persistence and activation of intratumoral T cells. PD-1 binds to its ligands PD-L1 and PD-L2, resulting in apoptosis of activated T-cells. Tumor cells are associated with persistently high PD-1 expression leading to T-cell exhaustion and hence, blockade of this pathway is an attractive therapeutic strategy. Various antibodies targeting these pathways are currently being studied in lymphoma. Nivolumab, an anti- PD-1 antibody, has been granted Breakthrough Therapy Designation by the US FDA for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant and brentuximab. The clinical development of other checkpoint inhibitors in lymphoma is ongoing. In this article, we summarize the current clinical development of these novel agents in lymphoid malignancies.


Lymphoma is the most common hematologic malignancy in the United States with an estimated 81,000 new cases of Hodgkin (HL) and non-Hodgkin lymphoma (NHL) combined and 21,000 deaths in 2015.1 NHL is the sixth most common type of cancer in both males and females, accounting for 5% and 4% of new cancer cases, respectively.1 Survival rates for both HL and NHL have improved significantly over the past several decades; however, outcomes continue to be poor in patients with relapsed/refractory disease.2 Recently, the introduction of novel targeted agents has ushered in a new era in management of lymphomas, especially in the relapsed/refractory setting and in frail, elderly patients with multiple comorbid conditions who are unable to tolerate cytotoxic combination chemotherapy and presents an interesting field for further research.

The immune system plays a key role in the surveillance, detection, and elimination of cancer cells. The curative role of immune therapy has long been recognized in patients with hematologic malignancies, with a prime example being allogeneic stem-cell transplantation. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance. In addition, they modulate the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage.3 Checkpoint inhibitors act by “releasing-the-brakes” on the patient’s immune system rather than targeting the tumor directly, and have demonstrated clinically meaningful results in various solid malignancies (ie, melanoma, renal cell carcinoma, lung cancer). This therapeutic strategy emerged from the recognition that tumors can evade the host immune system by usurping immune checkpoint pathways such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. In this review, we discuss the mechanism of action and clinical development of various checkpoint inhibitors in lymphoma.

Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4)

CTLA-4, the first immune checkpoint receptor to be clinically targeted, is expressed exclusively on T cells and primarily regulates the amplitude of the early stages of T cell activation.3 CTLA-4 downregulates T cell activity and leads to a decrease in the antitumor immune response.4-6 The significance of CTLA-4 in maintaining normal immunologi- cal homeostasis was confirmed by the findings that CLTA-4 deficient mice die from fatal lymphoproliferative disorders.7 Blocking CTLA-4 therefore promotes the persistence and activation of intratumoral T cells.8

Primarily, CTLA-4 counteracts the activity of the T-cell co-stimulatory receptor CD28. CD28 and CTLA-4 share identical ligands: CD80 (also known as B7-1) and CD86 (also known as B7-2). CD28 does not affect T-cell activation unless the T cell receptor (TCR) is first engaged by a cognate antigen. Once antigen recognition occurs, CD28 signaling strongly amplifies TCR signaling to activate T cells.3 Since CTLA-4 has a much higher overall affinity for both ligands, its expression on the surface of T cells dampens the activation of T cells by outcompeting CD28 in binding CD80 and CD86, as well as actively delivering inhibitory signals to the T cells.4-6 CTLA-4 also confers “signaling-independent” T- cell inhibition through the sequestration of CD80 and CD86 from CD28 engagement, as well as active removal of CD80 and CD86 from the antigen-presenting cell (APC) surface.9

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The Emerging Role of Checkpoint Inhibitors in Lymphoid Malignancies
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