Breast cancer future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

Medical investigational therapies are a wide range of new generations of targeted therapy, cancer vaccines, oncolytic virotherapy, gene therapy, and immunotherapy. Novel surgical and radiation techniques are also under investigation. A new generation of clinical trials (adaptive trials) are already being used in the war against breast cancer (i.e. I-SPY 2).

Immunotherapeutic interventions

Generally, cancer immunotherapy refers to immune checkpoint inhibitors and cytokines, adoptive cell therapy, and cancer vaccines.

Immune checkpoint inhibitors

Programmed cell death protein 1 (PD-1)

• Programmed cell death protein 1 (PD-1) is an inhibitory immune checkpoint inhibitor that limits T-cell effector function within tissues, and it is expressed on the surfaces of immune effector cells (T-cells, B cells, NK cells, DCs, and many TILs) and has two known ligands, namely, PD-L1 and PD-L2.

• Anti-PD-1 antibodies (Pembrolizumab, JS001, PDR001, and Nivolumab)
• Anti-PD-L1 antibodies (Atezolizumab and Durvalumab)

Anti-CTLA-4 antibodies (Ipilimumab and Tremelimumab)

• Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a T-cell inhibitory receptor that is expressed on activated CD8+ T cells and CD4+ regulatory T cells that express CD25 and Foxp3.
• Immune checkpoint inhibitors might be combined with targeted therapy (i.e Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors

Adoptive cell therapy

• Adoptive cell therapy is defined as the induction of anti-tumor immune responses via the isolation of highly active and tumor-specific lymphocytes, such as tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), Th cells, NK and Dendritic cells (DCs).

• Chimeric antigen receptors T-cell-based therapy
• T cell receptors (TCRs)—engineered T cells

Cancer vaccines

• Cancer-testis antigens (CTA) as a vaccine target
• Personalized peptide vaccination (PPV)
• Antigen-presenting cell (APC) and DC-based tumor vaccination

Antibody–drug conjugates (ADC)

• Utilization of monoclonal antibodies that recognize TAAs/TSAs and preferably internalizes when bound to the tumor cells to deliver highly potent cytotoxic agents.

Sacituzumab govitecan

• It is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.
• Each antibody having on average 6.7 molecules of SN-38 attached.
• SN-38 is too toxic to administer directly to patients, but the linkage to an antibody allows the drug to specifically target cells containing Trop-2.
• In in February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.

Exosomes

• Exosomes are mall 30–100 nm sized extracellular vesicles
• They are present in many eukaryotic fluids (normal and malignant)
• Particles that encapsulate contents, such as microRNAs.
• Exosome messaging contributes to:

• TME interactions, including:

• Immune suppression and immune escape,
• Invasive growth, adhesion, angiogenesis,
• Radiation resistance, chemo-resistance
• Genetic intercellular exchange,
• May manipulate tumor progression and metastatic cascade

Endoxifen

• Endoxifen is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group. It is an active metabolite of tamoxifen and has been found to be effective in patients that have failed previous hormonal therapies (tamoxifen, aromatase inhibitors, and fulvestrant).

Fenretinide

Fenretinide, a retinoid, is also being studied as a way to reduce the risk of breast cancer (retinoids are medications related to vitamin A).

Adaptive clinical trials such as I-SPY 2

• I-SPY 2 is an adaptive clinical trial of multiple Phase 2 treatment regimens combined with standard chemotherapy.
• I-SPY 2 linked 19 academic cancer centers, two community centers, the FDA, the NCI, pharmaceutical and biotech companies, patient advocates and philanthropic partners.
• The trial is sponsored by the Biomarker Consortium of the Foundation for the NIH (FNIH) and is co-managed by the FNIH and QuantumLeap Healthcare Collaborative.
• I-SPY 2 was designed to explore the hypothesis that different combinations of cancer therapies have varying degrees of success for different patients.
• Conventional clinical trials that evaluate post-surgical tumor response require a separate trial with long intervals and large populations to test each combination. Instead, I-SPY 2 is organized as a continuous process. It efficiently evaluates multiple therapy regimes by relying on the predictors developed in I-SPY 1 that help quickly determine whether patients with a particular genetic signature will respond to a given treatment regime.
• The trial is adaptive in that the investigators learn as they go, and do not continue treatments that appear to be ineffective.
• All patients are categorized based on tissue and imaging markers collected early and iteratively (a patient's markers may change over time) throughout the trial so that early insights can guide treatments for later patients.
• Treatments that show positive effects for a patient group can be ushered to confirmatory clinical trials, while those that do not can be rapidly sidelined.
• Importantly, confirmatory trials can serve as a pathway for FDA Accelerated Approval.
• I-SPY 2 can simultaneously evaluate candidates developed by multiple companies, escalating or eliminating drugs based on immediate results. Using a single standard arm for comparison for all candidates in the trial saves significant costs over individual Phase 3 trials.
• All data are shared across the industry.
• As of January 2016, I-SPY 2 is comparing 11 new treatments against 'standard therapy' and is estimated to complete in Sept 2017. By mid-2016 several treatments had been selected for later stage trials. (Clinical trials website: https://www.clinicaltrials.gov/ct2/show/NCT01042379)

Transcription factors

• NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility at the basis of metastasis formation.
• Indeed, NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma and NFAT3 (NFATc4) is an inhibitor of cell motility.
• NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin-2 to increase breast cancer cell invasion and NFAT3 inhibits Lipocalin-2 expression to blunt the cell invasion.
• NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2.

Cryoablation

• As of 2014 cryoablation is being studied to see if it could be a substitute for a lumpectomy in small cancers.
• There is tentative evidence in those with tumors less than 2 centimeters.
• It may also be used in those in who surgery is not possible.
• Another review states that cryoablation looks promising for early breast cancer of small size.
• New research also demonstrated promising results for the combination of cryotherapy and immune modulation as it may help prevent tumor recurrence.