NHS-IL12 and bintrafusp alfa combination therapy enhances antitumor activity in preclinical cancer models

Xu, Chunxiao; Marelli, Bo; Qi, Jin; Qin, Guozhong; Yu, Huakui; Wang, Hong; Jenkins, Molly H.; Lo, Kin-Ming; Lan, Yan

doi:10.1016/j.tranon.2021.101322

Cited by 12 publications

(8 citation statements)

References 55 publications

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“…Increases in T and NK cells were observed peripherally as well. This combination was also shown to decrease metastatic disease in 4T1 tumors ( 46 ). Overall, the combination of NHS-IL12 with other therapeutics such as ICIs and vaccine therapies, induces synergistic antitumor effects including immune stimulation and infiltration into tumors.…”

Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 97%

“…This combination elicited synergistic antitumor efficacy associated with increased immune infiltration and expansion of Th1 cytokines, tumor-specific immune memory, CD8 + T and NK cell proliferation, and enhancement of tumor antigen-specific CD8 + T cells ( 43 , 44 ). Subsequent studies examined the combination of NHS-IL12 with bintrafusp alfa in multiple preclinical tumor models ( 45 , 46 ). Bintrafusp alfa is a first-in-class bifunctional fusion protein of monoclonal human IgG1 antibody blocking PD-L1 fused to TGFβRII extracellular domains, thereby sequestering the immunosuppressive cytokine, TGFβ ( 45 , 47 ).…”

Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 99%

“…Bintrafusp alfa is a first-in-class bifunctional fusion protein of monoclonal human IgG1 antibody blocking PD-L1 fused to TGFβRII extracellular domains, thereby sequestering the immunosuppressive cytokine, TGFβ ( 45 , 47 ). The combination of NHS-IL12 and bintrafusp alfa elicited significant tumor homing of effector memory CD8 + T cells, tumor-specific immunity, increased survival, and anti-metastatic effects and development of protective immune memory ( 45 , 46 ). The addition of the vaccine PDS0101 targeting HPV16 E6/E7 to the combination of NHS-IL12 plus bintrafusp alfa was investigated in two human papillomavirus E6 and E7 positive (HPV E6/E7 + ) tumor models, TC-1 (lung carcinoma) and mEER (oropharyngeal squamous cell carcinoma).…”

Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 99%

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Preclinical and clinical studies of a tumor targeting IL-12 immunocytokine

Minnar,

Lui,

Gulley

et al. 2024

Front. Oncol.

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The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel cancer therapies that can provide clinical benefit for most patients with solid malignancies, which harbor innate or acquired resistance to ICIs. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy given its direct stimulatory effects on innate and adaptive immunity. However, unfavorable pharmacokinetics and a narrow therapeutic index render recombinant IL-12 (rIL-12) less attractive as a cancer therapy. NHS-IL12 is a fusion protein of IL-12 and NHS76 (human IgG1) antibody engineered to target single and double stranded DNA present in necrotic areas solid tumors. In preclinical tumor models, NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated clinically in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. Here we review the preclinical and clinical studies involving NHS-IL12 for the treatment of solid malignancies.

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Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 97%

Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 99%

Section: Preclinical Studies Involving Nhs-il12mentioning

confidence: 99%

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Preclinical and clinical studies of a tumor targeting IL-12 immunocytokine

Minnar,

Lui,

Gulley

et al. 2024

Front. Oncol.

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“…As a result of the role TGF-β plays in both tumor propagation and metastasis, there has been interest in combining TGF-β blockade with additional immunotherapeutic approaches. This includes a significant interest in concurrent CTLA-4 or PD-1/PD-L1 blockade [31][32][33], as well as combinations with immunocytokines [34], cytokine/chemokine blockade [35,36], oncolytic viruses [37], autologous tumor vaccination [38], and adoptive cell therapy [39]. The majority of these are outside the scope of this focused review.…”

Section: Importance Of the Transforming Growth Factor β (Tgf-β) Pathwaymentioning

confidence: 99%

Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

Tschernia

Gulley

2022

BioDrugs

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Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti-TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

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“…Several preclinical studies have explored the combination of TGFβ and PD-1/PD-L1 inhibition as cancer therapy with uniformly positive results. However, as this approach has begun to emerge in clinical trials, progress has been difficult, with most trials failing to recapitulate the successes observed in animal models 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ( Table 1 ). Here, we summarize key clinical trials exploring concomitant TGFβ and PD-1/PD-L1 signal inhibition in solid tumors.…”

Section: Introductionmentioning

confidence: 99%