Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.

Immune checkpoints (ICs) are molecules implicated in the fine-tuning of immune response via co-inhibitory or co-stimulatory signals, and serve to secure minimized host damage. Targeting ICs with various therapeutic modalities, including checkpoint inhibitors/monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and CAR-T cells has produced remarkable results, especially in immunogenic tumors, setting a paradigm shift in cancer therapeutics through the incorporation of these IC-targeted treatments. However, the large proportion of subjects who experience primary or secondary resistance to available IC-targeted options necessitates further advancements that render immunotherapy beneficial for a larger patient pool with longer duration of response. B7-H3 (B7 Homolog 3 Protein, CD276) is a member of the B7 family of IC proteins that exerts pleiotropic immunomodulatory effects both in physiologic and pathologic contexts. Mounting evidence has demonstrated an aberrant expression of B7-H3 in various solid malignancies, including tumors less sensitive to current immunotherapeutic options, and has associated its expression with advanced disease, worse patient survival and impaired response to IC-based regimens. Anti-B7-H3 agents, including novel mAbs, bispecific antibodies, ADCs, CAR-T cells, and radioimmunotherapy agents, have exhibited encouraging antitumor activity in preclinical models and have recently entered clinical testing for several cancer types. In the present review, we concisely present the functional implications of B7-H3 and discuss the latest evidence regarding its prognostic significance and therapeutic potential in solid malignancies, with emphasis on anti-B7-H3 modalities that are currently evaluated in clinical trial settings. Better understanding of B7-H3 intricate interactions in the tumor microenvironment will expand the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.

The emergence of immune checkpoint inhibitors has revolutionized the landscape of cancer treatment in the modern era. However, cutaneous immune‐related adverse events (cirAEs) are common, significantly affecting patients' quality of life and often leading to treatment discontinuation, which may compromise oncological outcomes. Dupilumab, an immunoglobulin G4 (IgG4) human monoclonal antibody targeting interleukin (IL)‐4 and IL‐13 receptors, is widely used for dermatologic conditions but remains unapproved for cirAEs due to the limited and scattered supporting evidence. This review aimed to summarize the available evidence regarding the use of dupilumab for the management of cirAEs. A systematic review was conducted using MEDLINE/PubMed, Scopus, and Web of Science in adherence to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. In total, 25 publications met the eligibility criteria and were included, reporting 136 patients who were diagnosed with 140 cirAEs and were treated with dupilumab. The most frequently treated cirAEs were eczematous rashes, bullous pemphigoid, and maculopapular/morbilliform rashes. Dupilumab was found to be highly effective, with most patients achieving complete or partial responses, even when affected by two concomitant cirAEs. An acceptable safety profile was demonstrated regarding both adverse events and oncological safety, with no additional concerns to be raised. The findings may be encouraging but are limited by the relatively small number of patients treated and the nature of the included studies, with most of them being case reports and case series. More research is warranted, along with more clinical studies, prospective in design, focused on relevant clinical outcomes of this dupilumab‐treated subset of patients.

Background: Primary cutaneous B‐cell lymphomas (PCBCLs) are rare cutaneous neoplasms with limited literature regarding treatment options and associated treatment outcomes. This study aimed to investigate and present real‐world treatment outcomes in patients with PCBCLs.Methods: All patients with PCBCL who were treated in five major referral centers for cutaneous lymphoma in Greece over 10 years were retrospectively included with their baseline characteristics and treatment‐associated outcomes collected and analyzed.Results: In total, 235 PCBCL patients, of whom 125 (53.2%) were females, were included. The median age at diagnosis was 60 years (IQR 47–72), and the median follow‐up duration was 3 years (IQR 1.3–6.4). The most common subtype was primary cutaneous marginal zone lymphoma (PCMZL) (52.3%), followed by primary cutaneous follicle center lymphoma (PCFCL) (40.9%), and primary cutaneous large B‐cell lymphoma, leg type (PCDLBCL, LT) with 16 (6.8%) cases. Complete responses (CRs) were observed in 77.3% after first‐line treatment. Both radiotherapy (RT) and surgical excision (SE) achieved superior outcomes, with 88.9% and 89% achieving CR, respectively. Relapses occurred in 22.6% of initial complete responders. The median time to the next treatment (TTNT) for the PCMZL and PCFCL was 349 days. RT and topical/intralesional steroids demonstrated longer TTNT compared to SE (445 and 359 vs. 154 days). For PCMZL and PCFCL, the 1‐year progression‐free survival (PFS) was 84.2% (75.7–89.9) and 85% (75.1–91.2), and the 5‐year PFS was 66.5% (55.2–75.5) and 58.8% (44.4–70.7), respectively.Conclusions: PCBCLs have favorable outcomes. RT demonstrates significantly increased TTNT compared to SE, suggesting RT as the preferable option. After careful evaluation, “watch and wait” may be a reasonable option for asymptomatic patients.