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PD-1 Pathway Blockade May Shape the Future of Hodgkin Lymphoma Therapy

Jane de Lartigue, PhD
Published: Wednesday, Jan 14, 2015

Amid increasing success for immune checkpoint blockade strategies in anticancer therapies, agents that target components of the programmed death-1 (PD-1) pathway are poised to make an impact on the treatment of patients with hematologic malignancies, particularly Hodgkin lymphoma (HL). 

Early clinical trial success and preclinical evidence has created a huge buzz in the research community, with multiple reports of astounding and durable responses in patients with HL, prompting the FDA to award breakthrough therapy status to nivolumab (Opdivo) in an HL setting. Data recently presented at the 2014 American Society of Hematology Annual Meeting (ASH) has reinforced excitement over nivolumab and the anti-PD-1 agent pembrolizumab (Keytruda) in certain subtypes of the malignancy. 

PD-1 Pathway Activity and Nivolumab Mechanism of Action

PD-1 Pathway Activity and Nivolumab Mechanism of Action

INF-κB indicates nuclear factor-Kappa B; IFNy, interferon gamma; IFNyR, interferon-gamma receptor; MHC, major histocompatibility complex. Adapted from Nourkeyhani H, George S. J Targeted Ther Cancer. 2014;3(5):46-50. www.targetedonc.com.

Enthusiasm over the potential for PD-1 inhibitors in blood cancers comes amid the continuing efficacy of therapies built on immune checkpoints, a plethora of inhibitory pathways that play a key role in regulating the duration and amplitude of the immune response and are co-opted by tumors as a means to evade the immune system.

Immune checkpoint inhibitors targeting components of these pathways have transformed the treatment landscape for metastatic melanoma. Ipilimumab (Yervoy), which inhibits cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), was the first such agent that the FDA approved in melanoma in 2011. Over just four months last year, the agency approved two PD-1 inhibitors, both pembrolizumab and nivolumab, for patients with metastatic disease. 

While PD-1 blockade has already been successfully exploited in patients with metastatic melanoma, their potential efficacy in a range of different solid tumors, notably non–small cell lung cancer (NSCLC) and bladder cancer, has really set these agents apart from other forms of immunotherapy. Now, the range of tumor types where PD-1 pathway agents are being explored is expanding in hematologic malignancies (Table 1). 

Immune Subterfuge: Exploiting Checkpoints 

Tumor cells express many unique antigens on their surface that make them vulnerable to the host’s immune system. Therefore, survival of cancer cells depends on their ability to evade the antitumor immune response initiated by the host. A key mechanism of immune evasion is the direct inhibition of cytotoxic T cells. In this context, immune checkpoint pathways have emerged as important mediators of this evasive capacity. 

Table 1. Ongoing PD-1/PD-L1 Trials In Hematologic Malignancies


Agent Industry Sponsor Ongoing Trials (clinicaltrials.gov identifier)
MEDI-0680 (AMP-514) MedImmune/ AstraZeneca Phase IB/II—In combination with anti-CD19 antibody MEDI-551 in patients with relapsed/refractory aggressive B-cell lymphomas who have failed 1-2 prior lines of therapy (NCT02271945)

Phase I—In combination with MEDI-4736 in patients with advanced malignancies, including hematologic malignancies (NCT02118337)
MEDI-4736   MedImmune/ AstraZeneca Phase I—In patients with relapsed/refractory MDS after treatment with or who are intolerant to hypomethylating agents (NCT02117219)
Phase I—In combination with MEDI-0680 in patients with advanced malignancies, including hematologic malignancies (NCT02118337)

MPDL3280A

Genentech/Roche

Phase I—In combination with obinutuzumab in patients with relapsed/ refractory FL and DLBCL (NCT02220842)
Phase I—In patients with locally advanced/metastatic solid tumors or hematologic malignancies (NCT01375842)

Nivolumab 
(Opdivo)

Bristol-Myers Squibb

Phase II—In patients with classical HL after failure of ASCT (CheckMate-205; NCT02181738)
 
Phase II—In patients with relapsed/refractory FL who failed therapy with both CD20 antibody and an alkylating agent (CheckMate-140; NCT02038946)

Phase II—In patients with relapsed/refractory DLBCL after failure of ASCT or after failure of at least 2 prior multiagent chemotherapy regimens in subjects who are not candidates for ASCT (CheckMate-139; NCT02038933)

Phase IB—In combination with dasatinib in patients with CML (NCT02011945)

Phase I—Alone or in combination with ipilimumab or lirilumab (targets KIR)&nbrelapsed/refractory lymphoma and multiple myeloma (NCT01592370)
Pembrolizumab
(Keytruda)

Merck

Phase I/II—In combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (NCT02289222)

Phase I—In combination with lenalidomide and dexamethasone, and with lenalidomide alone, in patients with multiple myeloma (KEYNOTE-023;

NCT02036502)a

Pidilizumab (CT-011) CureTech Phase II—Alone or in combination with dendritic cell/myeloma vaccines following ASCT in patients with multiple myeloma (NCT01067287)b

Phase II—In combination with dendritic cell/AML vaccine following chemotherapy-induced remission in patients with AML (NCT01096602)

Phase I/II—In combination with lenalidomide in patients with relapsed/ refractory multiple myeloma (NCT02077959)
AML indicates acute myeloid leukemia; ASCT, autologous stem cell transplant; CTCL, cutaneous T-cell lymphoma; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; KIR, killer-cell immunoglobulin-like receptor; MDS, myelodysplastic syndrome. aCelgene is collaborating on this study. bOngoing but not recruiting participants.
T-cell activation is two-step process: antigen recognition, followed by the generation of an antigen-independent coregulatory signal that determines whether the T cell will be switched on or off in response to the antigen. This second step is overseen by the immune checkpoint pathways, which are either stimulatory or inhibitory. 
 

PD-1 is a cell–surface receptor belonging to the CD28 family of T-cell regulators that is expressed on activated T cells and other immune cells. Upon interaction with its ligands, PD-L1 and PD-L2, it initiates an inhibitory signaling network that switches off activated T cells and results in T cell exhaustion—a state of dysfunction that is defined by poor effector function, even in the presence of antigens.


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