Robust Antitumor Effects of Combined Anti–CD4-Depleting Antibody and Anti–PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice

Ueha, Satoshi; Yokochi, Shoji; Ishiwata, Yoichi; Ogiwara, Haru; Chand, Krishant; Nakajima, T.; Hachiga, Kosuke; Shichino, Shigeyuki; Terashima, Yuya; Toda, Etsuko; Shand, Francis H.W.; Kakimi, Kazuhiro; Ito, Satoru; Matsushima, Kouji

doi:10.1158/2326-6066.cir-14-0190

Cited by 66 publications

(90 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected, co-administration of CD8-depleting antibodies with the initial doses of anti-CTLA-4 and anti-PD-1 abrogated antitumor responses in all treatment groups. In contrast, depletion of CD4 + T cells enhanced antitumor responses in tumor-bearing mice treated with control and therapeutic mAbs, likely due to the loss of intratumoral Tregs [31]. …”

Section: Resultsmentioning

confidence: 99%

Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

et al. 2016

View full text Add to dashboard Cite

The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.

show abstract

Section: Resultsmentioning

confidence: 99%

Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Considering that anti–PD-1 also controls key T-cell inhibitory interactions between PD-L1 on APCs and PD-1 on T cells (17, 42) and that PD-1 limits CD4 T-cell clonal expansion in response to an immunogenic stimulus (43), it is not surprising that CD4 T cells are required for anti–PD-1/PD-L1 tumor response. However, another group has reported opposite observations, with increased antitumor effect seen with CD4 cell depletion combined with PD-1/PD-L1 blockade (44). Of note, none of the tumor models evaluated by this group was responsive to anti–PD-1/PD-L1 itself.…”

Section: Discussionmentioning

confidence: 99%

Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells

Moreno

Zaretsky

García-Díaz

et al. 2016

Cancer Immunology Research

119

View full text Add to dashboard Cite

The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN-/-). Anti–PD-1 or anti–PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor associated macrophages in the tumors after PD-1 blockade. Compared to YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression from chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages.

show abstract

“…There is emerging preclinical evidence of the possible benefit of combined CBT in solid tumors 62 and in HM, 63 and this approach has already met with clinical success in melanoma treatment. 64 Several trials are underway testing this approach in HM: for example, a phase 1 study is testing the combination of nivolumab 1 ipilimumab (NCT01592370), whereas another trial testing nivolumab 1 urelumab includes an NHL cohort (NCT02253992).…”

Section: Org Frommentioning

confidence: 99%

Immune checkpoint blockade in hematologic malignancies

Armand

2015

Blood

208

136

View full text Add to dashboard Cite

Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning.

show abstract

Robust Antitumor Effects of Combined Anti–CD4-Depleting Antibody and Anti–PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice

Cited by 66 publications

References 36 publications

Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells

Immune checkpoint blockade in hematologic malignancies

Contact Info

Product

Resources

About