brown university pre med ranking Immunotherapy emerges as treatment for t-cell lymphoma asco-sitc clinical immuno-oncology symposium

The molecular understanding of T-cell lymphocyte activation and inhibition established the opportunity for cancer immunotherapy. Malignant cells influence the tumor microenvironment by altering immuno-regulatory cells that reduce host immunity. 1 the PD-1 receptor and its ligands, PD-L1 and PD-L2, inhibit T-cell activation and proliferation. 2 the PD-1 pathway is critical in regulating effector T-cell response in tissues by suppressing T-cell activity to limit tissue damage. 3 tumor-infiltrating lymphocytes may express these ligands in an increased fashion and engage with the PD-1 pathway to escape an immune response. 4,5 enhanced PD-L1 expression carries a poor prognosis with respect to various solid tumor systems, and pathway-blocking antibodies (i.E., checkpoint inhibitors) have been demonstrated to expand immunity in these settings and provide durable clinical responses with acceptable toxicity profiles. 6-8

The spectrum and activity of the PD-1 pathway has also displayed significant clinical relevance in multiple hematologic malignancies. Hodgkin lymphoma has a genetic basis for PD-L1 overexpression, and its associated 9p24.1 amplification increases PD-L1 expression on tumor cells, which has demonstrated a favorable response to targeted PD-1 blockade. 9,10 nivolumab, a PD-1–blocking antibody, has shown remarkable antitumor activity in heavily pretreated patients with hodgkin lymphoma and an objective response rate of up to 87%. 11 PD-1 expression may impair B-cell tumor–associated functions in select B-cell non–hodgkin lymphoma subtypes, such as diffuse large B-cell lymphoma and follicular lymphoma. 12,13

Peripheral T-cell lymphoma is heterogeneous in nature, comprises 10% to 15% of non–hodgkin lymphomas, and is derived from post-thymic mature T cells. Brown university acceptance rate 2012 in the absence of randomized trials, management for peripheral T-cell lymphoma—outside of the unique treatment of select subtypes—often resembles aggressive B-cell lymphoma, with an anthracycline-based regimen such as CHOP or similar agents. Unlike B-cell lymphoma, treatment outcomes are poor and durable responses are difficult to achieve, with progression-free survival (PFS) ranging from 40% to 50%. 14,15

PD-L1 expression was seen in approximately 15% of patients with peripheral T-cell lymphoma and 27% of those with cutaneous T-cell lymphoma (CTCL). 16,17 notably, PD-L1 expression was increased in the tumor microenvironment of 39% of peripheral T-cell lymphoma cases and 73% of CTCL cases. 16,17 peripheral T-cell lymphoma was noted to have a 40% objective response rate (i.E., all partial response) to nivolumab among a small subset of patients who were heavily pretreated. 18 thus, ongoing evaluations are seeking to improve therapy responses. In this article, we present a brief review of immunotherapy and checkpoint blockade agents in this uncommon disease. Peripheral T-cell lymphoma, not otherwise specified

Peripheral T-cell lymphoma, not otherwise specified, is the most common subtype of peripheral T-cell lymphoma. Anthracycline-based intensive therapy is often followed by consolidation with autologous stem cell transplantation for responsive disease. Brown university administration however, up to 41% of patients have progressive disease during induction or prior to transplantation, and current second- and third-line therapies offer minimal impact on survival. 19 in a trial of 155 patients with T-cell lymphoproliferative disorders, of whom 65 patients had peripheral T-cell lymphoma, not otherwise specified, PD-L1 expression was observed in 17% of cases, while another study documented PD-1 immunoreactivity in up to 62% of patients, thus highlighting a potentially significant use for cancer immunotherapy. 16,20 cutaneous T-cell lymphoma

Mycosis fungoides (MF) is a skin-limited, patch/plaque disease, and sézary syndrome (SS) features more extensive erythrodermic skin involvement. Together, they constitute more than 50% of CTCL cases. 21 limited MF often has an indolent course with near-normal life expectancy. However, advanced MF and SS have overall survival (OS) rates of less than 5 years. 22 therapeutic modulation of the immune system by in situ vaccinations has demonstrated objective responses and disease control—with PD-L1–mediated inhibition of the immune response being critically involved in advanced stages of CTCL—highlighting the immunogenicity of the disease and the potential target for immune checkpoint inhibitors. 5,23 wilcox et al noted that among eight patients with MF/SS, three (27%) expressed PD-L1 positivity. 16,17,21 rook et al demonstrated that patients with early-stage CTCL may respond favorably to topical resiquimod—a toll-like receptor 7 agonist that modifies the immune response by recruiting and enhancing T cells into the skin at treated and untreated lesions. 24

Ipilimumab, a CTLA-4–blocking antibody that inhibits the suppression of the immune system, was documented to induce complete remission (CR) of MF in a patient treated for advanced melanoma. 25 the combination of nivolumab and ipilimumab displayed a similar clinical safety and efficacy when compared with nivolumab monotherapy among pretreated patients with CTCL and peripheral T-cell lymphoma. 26 A phase II trial of patients with MF and SS who were heavily pretreated and who received pembrolizumab—a monoclonal antibody that targets the PD-1 receptor—demonstrated a 38% objective response rate, with a 1-year PFS of 69%. 27

Finally, a phase I study of nivolumab in various subtypes of relapsed or refractory non–hodgkin lymphoma noted a 15% objective response rate in MF, but 0% among SS or other variants of CTCL. 18 clinical outcomes with immunotherapy in more rare subtypes of CTCL have otherwise not been documented. Brown university music anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) accounts for approximately 15% of peripheral T-cell lymphoma. The systemic type is divided into ALK-positive or ALK-negative disease, depending on the presence or absence of the ALK protein on the lymphoma cells. PD-L1 expression may be upregulated by ALK, and therefore is thought to increase with protein positivity. 16 some studies report up to 100% PD-L1 expression among this subtype of patients with ALCL. 6,28,29 CR with pembrolizumab was reported for one patient with relapsed ALK-negative ALCL following allogeneic hematopoietic stem cell transplantation. 30 rare subtypes

Angioimmunoblastic T-cell lymphoma makes up roughly 15% of peripheral T-cell lymphoma cases. PD-L1 expression has been reported in 5% of cases, but PD-1 positivity may be found in more than 90% of patients. 16,31 future clinical trials are needed to evaluate the role of checkpoint blockade treatment in this rare subtype of T-cell lymphoma.

Natural killer (NK)/T-cell lymphoma is a subtype of peripheral T-cell lymphoma that is relatively rare in the united states but more common in asian countries, and it is typically associated with an epstein-barr virus infection. Brown university cost A retrospective analysis by kwong et al showed pembrolizumab yielded CR rates of 71% and an objective response rate of 100% among seven patients with relapsed or refractory NK/T-cell lymphoma. 32 PD-L1 was strongly expressed (≥ 50%) among four patients with excellent responses. Similar responses were noted for three patients with relapsed NK/T-cell lymphoma treated with nivolumab. 33

Adult T-cell leukemia/lymphoma (ATLL) is a rare subtype of peripheral T-cell lymphoma that is commonly related to infection with the human T-cell lymphotropic virus type I. Miyoshi et al noted PD-L1 expressivity for ATLL lymphoma cells in 7.4% of 135 patients, which was associated with a poorer median survival when compared with patients with PD-L1 tumor–negative disease (7.5 vs. 14.5 months, respectively). 34 interestingly, PD-L1 was positive in 58.5% of nonmalignant cells of the tumor microenvironment, which led to an improved OS relative to PD-L1–negative stromal cells, at 18.6 months and 10.2 months, respectively. 34 the distinction in PD-L1 expression should be a useful guide for evaluating clinical outcomes and responses to immunotherapy. Concluding remarks

As our understanding of essential immunologic principles clinically expands, the impact and scope of immune checkpoint inhibitors may broaden to encompass more patients whose disease has not responded to conventional treatment. Clinical trials are extending immunotherapy options in multiple types of B-cell and T-cell lymphoma, 35 and they are encouraging patient participation that will increase the potential clinical benefits of both single-agent and combination immunotherapy and checkpoint blockade treatments.

About the authors: dr. Brown university cio gorshein is a third-year hematology/oncology fellow at the rutgers cancer institute of new jersey — robert wood johnson medical school. Dr. Devata is a hematologist at the university of michigan and ann arbor VA healthcare system.