A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

McArthur, Heather L.; Diab, Adi; Page, David B.; Yuan, Jianda; Solomon, Stephen B.; Sacchini, Virgilio; Comstock, Christopher; Durack, Jeremy C.; Maybody, Majid; Sung, Janice S.; Ginsberg, Arielle A.; Wong, Phillip; Barlas, Afsar; Dong, Zhiwan; Zhao, Chunsong; Blum, Brian; Patil, Sujata; Neville, Deirdre; Comen, Elizabeth; Morris, Elizabeth A.; Kotin, Alan; Brogi, Edi; Ye, Wen; Morrow, Monica; Lacouture, Mario E.; Sharma, Padmanee; Allison, James P.; Hudis, Clifford A.; Wolchok, Jedd D.; Norton, Larry

doi:10.1158/1078-0432.ccr-16-0190

Cited by 179 publications

(142 citation statements)

References 38 publications

(34 reference statements)

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“…Although ER- breast cancer, in particular basal and triple negative breast cancer, is considered the most immunogenic subtype, reports from immune checkpoint inhibitor clinical trials are not as encouraging. Early reports suggest metastatic breast cancer patients may benefit most from PD-1/PD-L1 blockade monotherapy in the first-line setting, or in combination with chemotherapy agents for second or third-line therapy with an objective response rate ranging from 10%-40% 9-11 (for review, see ref. 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Immune checkpoint inhibitors targeting cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) or its ligand (PDL-1) perform best in immunogenic cancers such as melanoma and non-small cell lung cancer 7,8 , but responses have recently been reported in triple negative/basal-like breast cancers 9–11 (for reviews see refs. 12,13 ).…”

Section: Introductionmentioning

confidence: 99%

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TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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“…Interestingly, treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing ICOS and a marked increase in the ratio of ICOS+ T cells to FoxP3+ Tregs – findings that likely signal immune activation secondary to CTLA-4. In a recent pilot study of 19 pre-surgical patients with breast cancer, the combination of cryoablation with single-dose ipilimumab (anti-CTLA-4) demonstrated favorable intratumoral and systemic immune effects (43). …”

Section: Ctla-4 In Breast Cancermentioning

confidence: 99%

Immunotherapy for Breast Cancer: What Are We Missing?

Vonderheide

Domchek

Clark

2017

Clinical Cancer Research

167

146

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The recent demonstration of modest single-agent activity of programmed death-ligand 1 (PD-L1) and programmed death receptor-1 (PD-1) antibodies in patients with breast cancer has generated hope that breast cancer can be made amenable to immunotherapy. Depending on the subtype of breast cancer, it is now clear in both primary and metastatic disease that the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to non-immune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neo-epitopes – factors linked to response to checkpoint blockade in other malignancies – are all relatively modest in breast cancer, compared to melanoma or lung cancer. Thus, in breast cancer, combinations of immune agents with non-redundant mechanisms of action are the high-priority strategies. For most breast cancers that exhibit relatively modest T cell infiltration, major challenges include immune suppression in the tumor microenvironment as well as failed or suboptimal T cell priming. Agents that trigger de novo T cell responses may be critical for successful development of cancer immunotherapy and immune prevention in breast cancer. Success may also require reaching beyond nonsynonymous mutations as the T cell epitopes to target, especially as numerous unmutated proteins were validated as breast cancer associated antigens in the pre-checkpoint era. A deeper understanding of the immunobiology of breast cancer will be critical for immunotherapy to become broadly relevant in this disease.

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“…In the cohort of non-TNBC (n=10 patients), 2 SD and 1 PR were observed. 97 Ipilimumab is a recombinant human IgG1 mAb against CTLA-4 that has been investigated in BC in association with cryoablation in patients with operable BC, before undergoing mastectomy 98 (table 3). This treatment approach was safe, with only one grade 3 AE reported (rash after ipilimumab) that did not delay preplanned surgery.…”

Section: Ctla-4 Blockadementioning

confidence: 99%

Targeting immune checkpoints in breast cancer: an update of early results

et al. 2017

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The immune tumour microenvironment has been shown to play a crucial role in the development and progression of cancer. Expression of gene signatures, reflecting immune activation, and the presence of tumour-infiltrating lymphocytes were associated with favourable outcomes in HER2-positive and triple-negative breast cancer. Recently, immunotherapy with immune checkpoint blockade induced long-lasting responses and improved survival in hard-to-treat malignancies (ie, melanoma and non-small cell lung cancer) and are changing treatment paradigms in a variety of neoplastic diseases. Immune checkpoint blockade has been evaluated in breast cancer, particularly in the triple-negative subtype, with promising results observed in monotherapy or in combination with chemotherapy in the metastatic and neoadjuvant settings. However, identification of patients who are most likely to benefit from immune checkpoint blockade remains challenging, with many patients not responding to treatments and a significant financial cost. The combination of immune checkpoint blockade with conventional cancer treatments such as chemotherapy, radiotherapy, targeted therapies or with other immunotherapies is a promising strategy to potentiate its efficacy in breast cancer although further research is required to effectively identify who will respond to these immunotherapies. In this review we report the most recent results that emerged from trials testing immune checkpoint blockade and potential predictive biomarkers and emphasise the new strategies that are under clinical development in breast cancer.

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A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women with Early-Stage Breast Cancer with Comprehensive Immune Profiling

Cited by 179 publications

References 38 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Immunotherapy for Breast Cancer: What Are We Missing?

Targeting immune checkpoints in breast cancer: an update of early results

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