Simultaneous Inhibition of PD-1 and LAG-3: the Future of Immunotherapy?

Abi-Aad, Sasha-Jane; Zouein, Joseph; Chartouni, Antoine; Naim, Nabih; Kourié, Hampig Raphaël

doi:10.2217/imt-2022-0185

Cited by 9 publications

(6 citation statements)

References 51 publications

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“…(8) Immune stimulators such as imiquimod, dacarbazine, and interferon may help increase CD8+ tumor-infiltrating lymphocytes within in ALM and thus increase the efficacy of the immune checkpoint inhibitors such as PD-1/PD-L1 inhibitor [ 5 ]. Furthermore, lymphocyte activation gene-3 (LAG-3) inhibitor as another checkpoint inhibitor that cause exhaustion of T cell has been found its efficacy in treating advance melanoma [ 9 ]. The combination of nivolumab plus relatlimab showed grater benefit with progression-free survival compared to inhibition of PD-1 alone (10.1 months vs 4.6 months) in treating unresectable or metastatic melanoma [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Acral lentiginous melanoma with multiple bone metastasis: case report

Chen¹,

Manvar²,

Chaudhry³

et al. 2023

Pan Afr Med J

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Acral lentiginous melanoma (ALM) is a type of melanoma that is traditionally seen on the soles of the feet, palms of the hand, and under the fingernails or toenails. It is the least frequently diagnosed melanoma among the four histologic subtypes of cutaneous melanoma, accounting for less than 5% of all cases. ALM is frequently diagnosed at late stages and has higher incidences in non-white populations in relation to the other forms of cutaneous malignant melanoma. The most common sites of metastases in melanoma are the skin and subcutaneous tissue followed by lung, liver, brain, and bone. Bone metastases from malignant melanoma usually occur in patients who already have widespread metastases. We present this paper as a unique case study of ALM lesion in an 84-year-old African American male presenting originally in the base of right fifth toe plantar aspect then found multiple bone metastases without any other organ involved.

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Section: Discussionmentioning

confidence: 99%

Acral lentiginous melanoma with multiple bone metastasis: case report

Chen¹,

Manvar²,

Chaudhry³

et al. 2023

Pan Afr Med J

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“…Anti‐PD‐1, anti‐PD‐L1, and anti‐CTLA‐4 agents that have been used in clinical trials for high‐risk non‐muscle‐invasive bladder cancer are written in boxes. Lymphocyte‐activation gene 3 (LAG‐3), 194 which binds to major histocompatibility complex class II (MHC ll), 189 and T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT), 192 , 193 , 194 which binds to binds to CD112/155, 191 are other suggested immune checkpoints that are yet to show results in clinical trials involving this subset of patients. BCG, Bacillus Calmette–Guérin; CTLA‐4, cytotoxic T‐lymphocyte antigen 4; DC, dendritic cells; LAG‐3, lymphocyte‐activation gene 3; MHC II, major histocompatibility complex class II; NK, natural killers; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death ligand 1; PML, polymorphonuclear leukocytes; TIGIT, T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain.…”

Section: Immune Checkpoints In Bladder Cancermentioning

confidence: 99%

“… 192 LAG‐3, PD‐1, and TIGIT are all co‐expressed in tumor‐infiltrating lymphocytes; thus, dual LAG‐3/PD‐1 or TIGIT/PD‐1 blockage may synergistically bypass immune resistance and potentiate treatment efficacy. 192 , 194 LAG‐3 and TIGIT can become the primary targets next to PD‐1 in the development of cancer therapy. However, clinical evidence on the use of anti‐LAG‐3 or anti‐TIGIT is lacking and is being explored in cohort C of KEYNOTE‐057.…”

Section: Future Perspectivesmentioning

confidence: 99%

Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

Hannouneh,

Hijazi,

Alsaleem

et al. 2023

Cancer Medicine

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BackgroundHigh‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette–Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle‐invasive bladder cancer (MIBC). Patients who are BCG‐unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.MethodsTo address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR‐NMIBC treated with immune‐related agents were retrieved from clinicaltrials.gov.Findings and Future PerspectivesExploratory treatments for BCG‐Unresponsive HR‐NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs—pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec‐vncg—have been FDA approved for the treatment of BCG‐unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long‐term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR‐NMIBC is essential for the discovery of new targets and the development of effective treatments.

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“…The different mechanism of action between LAG-3 and PD-1 or CTLA-4 highlights the importance of synergistic enhancement of its combined antitumor blockade with PD-1. 56 In Table 2 , clinical trials involving combined LAG-3 with PD-1, CTLA-4 checkpoints blockade, or with bispecific agents targeting LAG-3 are presented. In addition, several bispecific agents targeting LAG-3 deserve attention.…”

Section: Lymphocyte Activation Gene-3mentioning

confidence: 99%

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

Kamali,

Bautista,

Eisenhut

et al. 2023

Therapeutic Advances in Vaccines and Immunotherapy

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Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.

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Simultaneous Inhibition of PD-1 and LAG-3: the Future of Immunotherapy?

Cited by 9 publications

References 51 publications

Acral lentiginous melanoma with multiple bone metastasis: case report

Acral lentiginous melanoma with multiple bone metastasis: case report

Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

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