TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers.

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.

Experimental treatment strategies in primary cutaneous T-cell lymphomas.

PURPOSE OF REVIEW: Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or resident T cells. Effective treatments are limited, thus new therapies are in development to address the unmet medical need. RECENT FINDINGS: Recent studies uncovering the genetic alteration in cutaneous T-cell lymphoma have enhanced our understanding of the importance of the T-cell activation/survival pathways, dysregulated immune system, and the relevance of chromatin modification in the pathogenesis of CTCL. New advances in cancer immunomodulation such as with PD1/PD-L1 inhibitors and novel targeted antitumor therapies such as brentuximab vedotin and mogamulizumab as well as potential combination strategies are promising for improving clinical efficacy with manageable toxicity profile. SUMMARY: All these new therapeutic approaches have resulted in broadening the treatment landscape and a potential paradigm shift in the management of CTCL.

Antibody-Based Therapies for Peripheral T-Cell Lymphoma.

While antibody-based immunotherapeutic strategies have revolutionized the treatment of B-cell lymphomas, progress in T-cell lymphomas has suffered from suboptimal targets, disease heterogeneity, and limited effective treatment options. Nonetheless, recent advances in our understanding of T-cell biology, the identification of novel targets, and the emergence of new therapies provide hope for the future. In this review, we explore four areas of current and evolving antibody-based strategies for the treatment of peripheral T-cell lymphoma (PTCL): monoclonal antibodies (mAbs), bispecific antibodies (BsAs), chimeric antigen receptor T-cell therapy (CAR-T), and antibody-drug conjugates (ADCs). As part of this discussion, we will also include limitations, lessons learned, and potential future directions.

Maintenance therapy for CTCL: importance for prevention of disease progression.

There are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease.

Spindle-cell variant of primary cutaneous follicle center lymphoma spreading to the hepatobiliary tree, mimicking Klatskin tumor.

Primary cutaneous follicle center lymphoma (pcFCL) is an indolent type of primary cutaneous B-cell lymphoma (pcBCL) rarely disseminating to other organs. PcBCL with spindle-cell morphology has been described as a rare variant of pcFCL but the prognosis data of this variant is sparse. We report a rare case of spindle-cell pcFCL with CD20(+), CD79a(+), CD3(+), Bcl-6(+), Mum-1(-) and CD10(-) tumor cells that infiltrated the hepatic hilum, mimicking a Klatskin tumor. On the basis of the sparse published data on spindle-cell morphology of pcBCL, this growth pattern should elicit awareness of an increased risk of systemic involvement in the otherwise indolent pcFCL.

Association of Cardiovascular Disease in Patients with Mycosis Fungoides and Sézary Syndrome Compared to a Matched Control Cohort.

Mycosis fungoides/Sézary syndrome (MF/SS) produces a low-grade chronic inflammatory state that may be associated with an increased risk of cardiovascular (CV) events, as seen in other chronic, systemic dermatologic diseases. To assess this association, a retrospective, cross-sectional study was designed in which 421 patients with a biopsy-proven diagnosis of MF/SS were compared with a control cohort of 4,210 age-, gender-, and race-matched patients randomly selected from the National Health and Nutritional Evaluation Survey database. The MF/SS cohort had a 14% prevalence of CV events, which was not statistically different from the control population's prevalence of 13%. In the MF/SS cohort, a multivariable logistic regression model showed that older patients (OR = 1.05 for each year of age, 95% confidence interval = 1.02-1.07) and those diagnosed with hypertension (OR = 3.40, 95% confidence interval = 1.71-6.75) had a higher risk of a CV event (P < 0.001). Risk factors such as gender, race, smoking, diabetes, and obesity were not significantly associated with CV events. Findings suggest that in the MF/SS population, advancing age and hypertension are risk factors for CV events, requiring clinical recognition and management. In addition, further research is needed to understand the complex interplay of how chronic inflammation in MF/SS impacts the immune development of CV disease.

Disseminated Eruptive Blue Nevi in a Young Adult Patient.

Common blue nevi tend to be singular or localized, with multiple eruptive blue nevi being a rare occurrence. We report the case of a young adult who presented with multiple asymptomatic lesions that had appeared gradually over a few years. Physical examination revealed 30 distinct, blue-gray macules diffusely over the medial buttocks, lower back, and dorsal arms. Histopathology showed pigmented dendritic melanocytes with associated melanophages, features characteristic of blue nevus. This case demonstrates that eruptive blue nevi can present as numerous, disseminated lesions over multiple anatomic sites. Recognition of the various patterns of eruptive blue nevi and their benign nature can reduce unnecessary biopsies and work-up.

Update on Biology of Cutaneous T-Cell Lymphoma.

Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.

Oral Mucosal Pigmentation in a Patient With Mycosis Fungoides.

A 53-year-old woman with mycosis fungoides presented with hyperpigmentation of the oral mucosa. Examination of the mouth revealed multiple coalescing painless nonpruritic black macules and patches on the tongue, roof of the mouth, and buccal mucosa. What is your diagnosis?