Vaccine trials have historically not had much success in breast cancer, and research had been slowed by the advent of checkpoint inhibitors, said Emens, a professor of medicine in Hematology/Oncology, co-leader of the Hillman Cancer Immunology and Immunotherapy Program, and director of Translational Immunotherapy for the Women’s Cancer Research Center at the UPMC Hillman Cancer Center, during the meeting, which was hosted by the Physicians’ Education Resource® (PER®), LLC.
However, translational research has provided valuable insights into why that is, explained Emens, stating, “breast cancer is largely a cold tumor. [Additionally,] multiple layers of regulation within the tumor microenvironment can shut down tumor immunity, and beyond the tumor microenvironment, immune tolerance matters.”
Moreover, a minority of tumors have innate T-cell responses that can respond to checkpoint inhibitors, making vaccines, which can, under optimal circumstances, induce T cells that can reach the tumor microenvironment, a necessity for the success of immunotherapy in most cancers.
“If there are no T cells, there’s no way for checkpoint inhibitors to work, and that’s where cancer vaccines come in,” said Emens. “Cancer vaccines are developed as a variety of different platforms that deliver exogenous tumor antigens that translocate to the lymph nodes and prime and activate T cells.”
Leveraging Negative Trial Insights
In the phase 3 PRESENT trial (NCT01479244), investigators compared the HER2-peptide vaccine, nelipepimut-S (NP-S) plus granulocyte-macrophage colony-stimulating factor (GM-CSF; n = 376) with placebo plus GM-CSF (n = 382) as adjuvant therapy in patients with HER2-low breast cancer.
However, no significant difference in disease-free survival was reported between arms at a median follow-up of 16.8 months. In the NP-S arm, imaging detected 54.1% of recurrence events in asymptomatic patients vs 29.2% of recurrence events in the placebo arm (P = .069).2
In the phase 2 ABCSG 34 trial, investigators evaluated the MUC-1–specific vaccine, tecemotide as neoadjuvant therapy in patients with early-stage, HER2-negative breast cancer. The primary end point was residual cancer burden (RCB) 0/I vs II/III at surgery.
However, no significant difference in RCB 0/I rates between patients who did (36.4%) or did not receive (31.9%) tecemotide was reported in the overall study population (P =.40) nor in endocrine and chemotherapy-treated subgroups (25.0% vs 13.3%, respectively, P =.17; 39.6% vs 37.8%, respectively, P =.75).
Although on face value these trials indicate the lack of benefit of vaccines, they point also to clinical trial design issues, explained Emens, who recommended revisiting optimal patient selection, clinical trial end points, biomarker and immune response monitoring techniques, and vaccine combination partners.
Moreover, immune tolerance and suppression with regulatory T cells, myeloid-derived suppressor T cells, and tumor-associated macrophages represent additional barriers to tumor immunity, said Emens.
For example, findings from 2 preclinical studies similarly demonstrated that systemic immune tolerance limited the effectiveness of immunotherapy, and the administration of only a vaccine was not able to overcome immune tolerance in mice.4,5
However, the investigators also showed that the mice with immune tolerance who appeared to be unaffected by the vaccine derived HER2-specific CD8+ T-cell activity and subsequent tumor regression with the addition of PD-L1 blockade plus OX40 receptor activation4 and delayed tumor growth with the addition of cyclophosphamide, paclitaxel, and doxorubicin.5
“We translated this to the clinic and tested this approach using a human GM-CSF–secreting breast cancer vaccine composed of allogeneic breast tumor cells, SKBR3, and T47D,” said Emens.
The vaccine was given in sequence with cyclophosphamide and doxorubicin in the same way as in the mice in patients with estrogen receptor–positive metastatic breast cancer.6
Twenty-eight patients received at least 1 immunization, and 16 patients received 4 immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received the vaccine alone or with 200 mg/m2 of cyclophosphamide.
Notably, HER2-specific antibody responses were enhanced by 200 mg/m2 of cyclophosphamide and 35 mg/m2 of doxorubicin, but higher doses of cyclophosphamide suppressed immunity. The combination of 200 mg/m2 of cyclophosphamide and 35 mg/m2 of doxorubicin induced the highest antibody responses.
“[We learned that] the dose is really important; [in this case], only the low dose [of cyclophosphamide] helped. In contrast, with doxorubicin, it was the high dose that amplified the antibody responses,” said Emens.
Additionally, cyclophosphamide preferentially affected regulatory T cells relative to effector T cells, Emens added.
The working theory is that the approach decreases the suppressive regulatory T cells and sustains the effector T-cell population, creating a window for the vaccine to be effective, Emens explained.
Similar synergistic activity has been seen with the addition of a vaccine to cyclophosphamide and trastuzumab (Herceptin) in HER2-transgenic mice and patients with metastatic breast cancer,1 explained Emens.
In conclusion, Emens said that STING agonists represent another potential strategy to induce inflamed tumors, stating that “these agents are actively in the clinic now, primarily in combination with agents that target the PD-1 pathway.”
References
- Emens LA. Novel vaccines for early and metastatic breast cancer. Presented at: 20th Annual International Congress on the Future of Breast Cancer® East; July 16-17, 2021; virtual.
- Mittendorf EA, Lu B, Melisko M, et al. Efficacy and safety analysis of nelipepimut-s vaccine to prevent breast cancer recurrence: a randomized, multicenter, phase III clinical trial. Clin Cancer Res. 2019;25(14):4248-4254. doi:10.1158/1078-0432.CCR-18-2867
- Singer CF, Pfeiler G, Hubalek M, et al. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34). Eur J Cancer. 2020;132:43-52. doi:10.1016/j.ejca.2020.03.018
- Foote JB, Kok M, Leatherman JM, et al. A STING agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Cancer Immunol Res. 2017;5(6):468-479. doi:10.1158/2326-6066.CIR-16-0284
- Machiels JP, Reilly RT, Emens LA, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating-factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61(9):3689-3697.
- Emens LA, Asquith JM, Leatherman JM, et al. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol. 2009;27(35)5911-5918. doi:10.1200/JCO.2009.23.3494
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