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Hope Rises for Immunotherapy in Breast Cancer

Andrew D. Smith
Published: Wednesday, Mar 25, 2015

Checkpoints Explored

Determining “how” they work best will eventually entail testing combinations of immunotherapies that, logically, should produce synergies, but testing to date has mostly involved supplementing existing standards of care with a single vaccine or, in other cases, a single checkpoint inhibitor.

Regulators have approved three such compounds to date: ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo). The first of those drugs makes it harder for tumors to call off immune attack via the cytotoxic T-lymphocyte-associated protein–4 (CTLA-4) pathway. The others reduce similar communication via the programmed death receptor-1 (PD-1) pathway.

At present, all three agents are approved exclusively for melanoma, but they may work against other tumors. Both of the anti-PD-1 medications are already in late-stage trials against certain lung cancers and early-stage trials against breast cancer.

A phase 1b trial of pembrolizumab in metastatic triple-negative breast cancer produced an overall response rate of 18.5%.3 The experimental compound MPDL3280A also produced responses in a similar patient group.4

Such apparent effects may be explained, at least in part, by a finding from Mittendorf’s research group: 20% of all triple-negative breast tumors express the PD-1 ligand, PD-L1.5 PD-L1 expression levels are considered a potential biomarker for PD-1–targeted agents.

Given that triple-negative tumors respond so little to all existing treatments, significant progress against even 20% of them would be cause for celebration, but separate research suggests there are ways to increase PD-L1 expression on tumors and ways to boost the number of T cells available to attack the tumor.

“There are a lot of promising ideas for improving response rates and increasing the strength of those responses, though there is also concern that the relative lack of T cell activity inside the breast will effectively prevent a large percentage of patients from responding to checkpoint blockade,” Mittendorf said.

“Still, even if the latter idea proves right and response rates never exceed 20%, immunotherapy would still constitute a breakthrough in treatment. Only 20% of breast cancers express HER2 and nobody would call the treatments that target such tumors anything less than a breakthrough,” she said.


References

  1. Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients [published online June 6, 2014]. Ann Oncol. 2014;25(9):1735-1742.
  2. NIHClinicalTrialsRegistry.www.ClinicalTrials.gov.Identifier NCT01479244.
  3. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.
  4. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract PD1-6.
  5. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer [published online January 10, 2014]. Cancer Immunol Res. 2014;2(4):361-370.





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