Roswell Park Metastatic Breast Cancer Studies Focus on New Immunotherapies

Mateusz Opyrchal, MD, PhD

Assistant Professor of Medicine

Associate Director of the Early Phase Clinical Trials Program

Co-leader of the Adoptive Cellular Therapy Program

Co-leader of the Breast Disease Specific Research Group at Roswell Park Comprehensive Cancer Center, Buffalo, New York

Despite considerable advances and promising developments in recent years, metastatic breast cancer (mBC) continues to be a deadly disease. Although the first immune agonist was recently approved for patients with locally advanced or metastatic triple-negative breast cancer (mTNBC), the effectiveness of immunotherapy strategies in the treatment of mBC remains a work in progress.

Several strategies with a strong scientific basis are now under investigation, including many clinical trials under way at Roswell Park Comprehensive Cancer Center in Buffalo, New York. These secondgeneration immunooncology studies hold great promise for breaking through the known barriers highlighted by earlier research against this intractable disease.

Checkpoint Inhibition in MBC

Anti-PD-1 antibodies work by blocking the inhibitory signal from the tumor cells to CD8-positive T cells, preventing interaction of the PD-1 receptor and its ligands, PD-L1 and PD-L2.¹ Although these drugs have seen spectacular successes in the treatment of melanoma and are approved for multiple other cancers, the results in breast cancer studies have been disappointing.^2,3

In clinical trials using these agents as part of treatment for mTNBC, responses have been seen in 5% to 10% of patients, a statistic that highlights the difficulty of these approaches in this malignancy. Despite such low response rates, the patients who do respond often experience prolonged control of the disease, which shows the promise of immunotherapy approaches.

In March, the FDA approved the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) as a first-line treatment for patients with mTNBC expressing PD-L1 on tumor-infiltrating immune cells covering ≥1% of the tumor area. The approval is based on findings from the IMpassion 130 trial.⁴

Schmid et al reported that patients with PD-L1—positive mTNBC achieved median progression-free survival of 7.5 months with the atezolizumab combination compared with 5.0 months with nab-paclitaxel plus placebo (HR, 0.62; 95% CI, 0.49-0.78; P <.001). Median overall survival was 25.0 months versus 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86).⁵

However, early analysis of the data has not provided any evidence of long-term responses; the median duration of response in patients with PD-L1—positive tumors, after 12.9 months of median follow-up, was 9.2 months (95% CI, 7.5-11.9) with the atezolizumab combination versus 6.2 months (95% CI, 5.5-8.8) for chemotherapy alone.⁴

Targeting the Tumor Microenvironment

One of the main obstacles identified as a resistance mechanism to immunotherapy is the lack of breast cancer tumor infiltration by the PD1-expressing CD8-positive T cells that must be activated by PD-1 blockade to attack the cancer cells, resulting in the phenomenon of “cold” tumors. This is an area of intense research, with multiple approaches in active investigation to improve efficacy.

Our research team, which includes my Roswell Park Comprehensive Cancer Center colleagues Pawel Kalinski, MD, PhD, and Shipra Gandhi, MD, is attempting to address this by targeting abnormal signaling in the breast cancer microenvironment—specifically, mechanisms that attract immunosuppressive cells instead of antitumor immune cells.

This approach, which is based on Kalinski’s preclinical work, attempts to change the mTNBC microenvironment from cold to hot so that these tumors will be subsequently responsive to anti-PD1 therapy.^6-11 This research led to a novel clinical trial (NCT03599453) that includes pretreatment with a regimen designed to change the breast cancer microenvironment signaling to allow CD8-positive T-cell infiltration so that these patients will respond well to subsequent pembrolizumab (Keytruda).

Adoptive Cell Strategies

Adoptive cell strategies including chimeric antigen receptor T-cell therapies have gained acceptance in the wider clinical world following the FDA approvals of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) for the treatment of patients with leukemia and lymphoma. Solid tumors, including mBC, present a new set of challenges because of their high antigenic heterogeneity and microenvironmental barriers to infiltration with adoptively transferred cells.

Manipulating dendritic cells is one strategy for overcoming both of these barriers. The goal with this area of immunotherapy is to generate effective antitumor CD8-positive T cells. Our team is working on using dendritic cell vaccines to allow for an effective immune response against mBC. Clinical trials are being prepared in collaboration with Moffitt Cancer Center in Tampa, Florida.

Using adoptive T-cell strategies is another approach that focuses on designing active T cells against specific targets present in cancer cells. We are focusing on T-cell—receptor T-cellbased adoptive cell therapies because they target a wider range of proteins. In collaboration with our colleagues from Roswell Park’s Center for Immunotherapy, led by Kunle Odunsi, MD, PhD, and Richard Koya, MD, PhD, we are in the process of developing a breast cancer–specific protocol targeting the NY-ESO-1 protein. We are awaiting completion of the ongoing phase I trial to assess safety of the treatment in locally advanced or stage IV solid tumors that express NY-ESO-1 (NCT02650986).

Together, these investigational approaches represent exciting prospects for finally breaking through the challenges that mBC has posed to date. Because this is an area of such dire clinical need in one of the most common cancer types in women, we greet the coming years with excitement and eagerly look forward to seeing the results from our own trials and many others from our colleagues around the globe.

References

1. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;(19):5300-5309. doi: 10.1158/1078-0432.CCR-13-0143.
2. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. Cancer Res.2017;77(13)(suppl; abstr 2986). doi: 10.1158/1538-7445.AM2017-2986.
3. Adams S, Schmid P, Rugo HS, Winer EP, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Oncol. 2017;35(suppl 15; abstr 1008). meetinglibrary.asco.org/record/152162/abstract.
4. Tecentriq [prescribing information]. South San Francisco, CA: Genentech, Inc; 2019. www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s019lbl.pdf. Accessed April 19, 2019.
5. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
6. Fujita M, Zhu X, Ueda R, et al. Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10 [erratum in Cancer Res. 2010;70(16):6683]. Cancer Res 2009;69(4):1587-1595. doi: 10.1158/0008-5472.CAN-08-2915.
7. Kalinski P, Okada H. Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors. Semin Immunol. 2010;22(3):173-182. doi: 10.1016/j.smim.2010.03.002.
8. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118(20):5498-5505. doi: 10.1182/blood-2011-07-365825.
9. Obermajer N, Urban J, Wieckowski E, et al. Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents. Nat Protoc. 2018;13(2):335-357. doi: 10.1038/nprot.2017.130.