PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice

Pan, Bin; Shang, Longmei; Liu, Cong; Gao, Jun; Zhang, Fan; Xu, Min; Sun, Zengtian; Li, Zhenyu; Xu, Kailin

doi:10.1111/ajt.16275

Cited by 9 publications

(4 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, at the doses tested, T cell function and total numbers were preserved in mice as well as Hodgkin lymphoma patients. This is supported by observations in other studies in which T cell function was preserved at therapeutic doses of JAKis, including preserved graft-versus-tumor effect in ruxolitinib-treated graft-versus-host disease ( 52 , 53 ). Previously, reports showed that PD-1 inhibition can be effective in individual patients treated with ruxolitinib ( 54 , 55 ) despite the general immunosuppressive effects of ruxolitinib ( 56 , 57 ).…”

Section: Resultssupporting

confidence: 85%

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

Zak,

Pratumchai,

Marro

et al. 2024

Science

View full text Add to dashboard Cite

Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti–PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.

show abstract

Section: Resultssupporting

confidence: 85%

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

Zak,

Pratumchai,

Marro

et al. 2024

Science

View full text Add to dashboard Cite

show abstract

“…However, at the doses tested, T cell function and total numbers were preserved in mice in vivo as well as Hodgkin lymphoma patients. This is echoed by observations in other studies in which T cell function was preserved at therapeutic doses of JAK inhibitors (54,55). Therefore, drug dosing is likely of key importance to the success of JAK inhibitors in the context of cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 88%

Myeloid reprogramming by JAK inhibition enhances checkpoint blockade therapy

Zak

Pratumchai

Marro

et al. 2022

Preprint

View full text Add to dashboard Cite

Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors' ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils. In a clinical trial of Hodgkin lymphoma patients resistant to checkpoint inhibitors, treatment with ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and levels of suppressive markers in myeloid cells but increased numbers of cytokine-producing T cells. These results support the therapeutic potential of JAK inhibition in combination with checkpoint inhibitors in cancer and highlight the potential of reshaped myeloid immunity to improve immunotherapy.

show abstract

“…With the aim to delineate the effect of anti-CD19 CAR T cell therapy, we used a syngeneic mouse model of A20 lymphoma as others and our previously described ( 18 , 19 ). As shown in Figure 1A , when the mice treated with CAR T cells reached initial remission and then relapsed after CAR T-cell injection, the samples were harvested for detection on days 15 and 42, respectively.…”

Section: Resultsmentioning

confidence: 99%

The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice

et al. 2023

Self Cite

View full text Add to dashboard Cite

Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase.

show abstract

PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice

Cited by 9 publications

References 42 publications

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

Myeloid reprogramming by JAK inhibition enhances checkpoint blockade therapy

The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice

Contact Info

Product

Resources

About