Immunotherapy in Breast Cancer Dr. Zahra Mozaheb Hematologist-Medical

 Immunotherapy in Breast Cancer Dr. Zahra Mozaheb Hematologist-Medical

Immunotherapy in Breast Cancer Dr. Zahra Mozaheb Hematologist-Medical Oncologist Immunotherapy in breast cancer There is no effective treatment for patients with invasive and metastatic breast cancer.

Cancer immunotherapy has emerge an important modality in addition to surgery, chemotherapy, radiotherapy and hormonal treatment. Immunotherapy holds substantial potential as a non-toxic, sustainable therapeutic option personalized to patients specific tumor characteristics. Enhancing the immune system to recognize and destroy tumor cells via personalized immunotherapy is an increasingly intriguing possibility in the treatment of breast cancer.

Breast cancer immunotherapy includes: antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy . PASSIVE IMMUNOTHERAPY:

antibody based passive immunotherapy has provided several successful treatments for breast cancer. The current mainstay of passive immunotherapy includes trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) Utilized in both the metastatic and adjuvant setting, trastuzumab, confers considerable benefit to both node-positive and high risk node-negative patients breast cancer patients.

The antibody pertuzumab has gained approval as a combination therapy with trastuzumab. As a second line treatment, T-DM1, a combination of trastuzumab antibody and cytotoxic agent, exhibits superiority to standard of care chemotherapy and has been approved for metastatic cancer no longer responsive to trastuzumab The subsequent phase III CLEOPATRA study examined trastuzumab and docetaxel chemotherapy with or without pertuzumab. The study population of HER2 overexpressing breast cancer patients boasted a 18.5 months progression free survival versus 12.4 months in the control group (p<0.001) with overall survival rates favoring the pertuzumab/trastuzumab treatment arm.

FDA approval of pertuzumab in combination with tratuzumab and docetaxel for HER2 overexpressing breast cancer followed this study. The phase III EMILIA trial was recently completed supporting both efficacy and safety of T-DM1 in HER2-overexpressing breast cancers. Active Immunotherapy: Checkpoint Blockade Agents Immunostimulatory mAbs exert their effect through the reactivation or elicitation of the immune response to tumor cells.

Immunotherapeutic strategy of great potential is blockade of inhibitory receptors such as cytotoxic T lymphocyte-associated protein 4 (CTLA- 4) and programmed cell death (PD-1). Modulating such regulators of immunity such as regulatory T cells (Tregs) and immune checkpoint pathways are novel methods of active immunotherapy with great therapeutic potential. By inhibiting CTLA-4 on Tregs, their inhibitory activity can be downmodulated and immune responses enhanced. The mAb, ipilimumab, inhibits binding to its natural ligand CD80/86, thus

blocking the negative activity of the CTLA-4 molecule and has received FDA approval for treatment in metastatic melanoma patients. Unfortunately, ipilimumab, as well as other CTLA-4 blockade agents, carry a high risk of life-threatening autoimmunity. antibodies specific to PD-1 in patients with advanced non-smallcell lung cancer, renal carcinoma, melanoma, ovarian cancer, and breast cancer were validated. The PD-1 blockade resulted in clinical response and a tolerable toxicity profile that appears to be better than ipilimumab.

Active Specific Immunotherapy: Cancer Vaccines Advances in techniques of passive cancer immunotherapy and early success in active immunotherapies have led to the development of cancer vaccines, an active and specific immunotherapeutic approach. An ideal vaccine should induce activation and proliferation of specific lymphocytes to stimulate both humoral and cellular immunity. The vaccine should induce immunologic memory while being safe, simple to administer, and widely exportable to the eligible population.

Provenge (sipuleucelT), the first true cancer vaccine, gained FDA approval for the treatment of hormone-resistance metastatic prostate cancer in 2010. No active specific immunotherapy, or cancer vaccine, is currently approved for the treatment of breast cancer. HER2 Vaccine Development Clinical evaluation of HER2 targeting breast cancer vaccine platforms has included peptide, protein, plasma DNA, and dendritic based vaccines.

The earliest trials of single epitope peptide vaccinations occurred in the 1990s. More recent trials are utilizing longer and/or multiple peptide sequences aimed to produce a more effective, complete immune response in the adjuvant setting. Additional challenges include the identification of the ideal tumor associated antigen (TAA), the basis of peptide vaccination, given the complex mechanisms of immune escape and tolerance following malignancy. The ultimate goal is to create personalized vaccine therapy specific to the individuals tumor biology.

Nelipepimut-S (Neuvax) High percentages of breast, ovarian, lung and colorectal cancer patients have been found to have preexisting immunity to nelipepimutS. Phase I trials of nelipepimut-S were conducted in combination with different immunoadjuvants. These trials demonstrated the peptide to be safe and capable of eliciting a peptide-specific CTL immune response in metastatic breast, ovarian, and colorectal cancer patients. As stated earlier, the majority of early clinical work with this peptide

vaccine targeted patients with advanced and metastatic disease, a strategy that proved disappointing given issues of immunosuppression and tolerance. NeuVaxTM phase I trials in both node-positive and node-negative breast cancer patients at high risk of recurrence who were clinically disease-free were initiated. All patients had completed standard of care with surgery, chemotherapy, and radiation treatment as indicated. Patients were allowed concomitant hormonal therapy during the trial.

HLA-A2 positive patients were vaccinated while HLA-A2 negative patients were followed as controls given HLA-A2 status has not been shown to impact prognosis in breast cancer. Importantly, patients with any level of HER2 expression were enrolled. Results showed the vaccine to be well tolerated with incouraging immunologic results. NeuVaxTM was shown again to be safe but more importantly effective with a significantly greater disease free survival (DFS) rate in the vaccinated group at 18 months (92.5 vs. 77%, p=0.04); although, this effect waned at 24 months.

Booster inoculations were enacted into the trial after initiation of the study protocol based on observations of waning immunity in trial patients a year or more after completion of the vaccine series. The additional inoculations were well tolerated and were effective in maintaining nelipepimut-S-specific immunity. In addition, a trend towards decreased disease recurrence occurred in the optimally boosted patients who received their initial booster inoculation less than 6 months after completion of the primary vaccine series. At 24 months follow-up, DFS was 94% versus 79.4% in the control population, p=0.0441.

Given the benefit toward HER2 expressing (IHC 1-2+) subjects within the phase II trial , our group is currently focused on the adjuvant PRESENT trial, a prospective, randomize phase III clinical trial to test the NeuVaxTM vaccine (NCT 01479244). Currently being conducted in the United States and internationally, this randomized study enrolls HLA-A2/ A3 positive, node positive, HER2 expressing (IHC 1-2+) patients who are clinically free of disease after standard of care treatment. All patients will be optimally dosed and boosted. The primary endpoint is three years disease-free survival. Enrollment was completed in 2014. Combination Therapy

MHC Class II binding and promiscuous peptides are being investigated as possible adjunct therapies in conjunction with nelipepimut-S to elicit a CD4+ T cell response to sustain immunologic memory . A helper peptide combination utilizing longer MHC Class II peptides containing MHC Class I peptides (including nelipepimut-S), have been used to vaccinate HLA-A2+ patients with demonstration of post-inoculation immunity. An additional approach is the combination of cancer vaccines with mAb therapies. Given that molecular immune checkpoints such as CTLA-4 and PD1/PD1L play key roles in maintaining self-tolerance and mechanisms by which tumors cells can escape immune attack, this combination therapy may enhance a vaccine approach. Additionally, vaccines may be used synergistically with passive immunotherapy directed against the same target antigen. A phase I/II study examining administration of a HER2-directed vaccine in combination with trastuzumab in stage IV

breast cancer patients did not result in additional toxicity. Conclusion New immunomodulatory agents and vaccines show promise in reversing the immunosuppression caused by established tumors. Although breast cancers vaccines have been largely unsuccessful in past clinical trials, the majority of these trials occurred in the setting of late-stage metastatic disease, an unfavorable environment for agents designed to prevent, as opposed to treat, disease. With current trials focused on the adjuvant settings,

immunogenicity is now showing correlation with clinical response. The future of breast immunotherapy and research will continue to be a dynamic field as understanding of the complexity of tumor progression grows. Immunotherapeutic approaches in triplenegative breast cancer Breast cancers that are negative for ER, PR and HER2 are considered as triple-negative breast cancer (TNBC) and represent 1520% of newly diagnosed cases.

Compared with other forms of breast cancer, TNBC is associated with a younger age at diagnosis advanced stage at diagnosis, increased risk of visceral metastasis and poorer outcome. Because TNBC lacks a therapeutic target, patients do not benefit from endocrine therapy or HER2-targeted therapy. Accordingly, TNBC remains an important challenge in todays clinical practice. Heterogeneity of TNBC It has been suggested that approximately 70% of TNBCs present a basallike gene expression profile. At the histopathological level, TNBC (defined by IHC) and basal-like breast

cancers (defined by gene expression) share several characteristics, such as high histologic grade, pushing borders of invasion and stromal lymphocytic infiltrates. Also, both TNBC and basal-like breast cancers show links with BRCA1-mutated breast cancers and the BRCA1 pathway in general. Accordingly, up to 90% of BRCA1-associated tumors are TNBC by IHC. Expression of basal CKs (i.e. CK5/6, CK14, and CK17), EGFR and C-kit markers in TNBC is associated with shorter survival compared with the remaining patients with TNBC.

By using gene expression profiling TNBC molecular subtypes included two basal-like, two mesenchymal, a luminal androgen-receptor positive and an immunomodulatory subtype. The identification of a TNBC subtype characterized by elevated expression of immune genes suggests that some patients may benefit from immune-based therapies. Over recent years, overwhelming data have revealed the importance of tumorinfiltrating lymphocytes (TILs) in controlling the clinical progression of various epithelial cancers. In colorectal cancers, for instance, immune-scoring determined by IHC of intratumoral CD8+ T cells has shown superior prognostic power than standard tumor staging

(AJCC/UICC-TNM classification) methods In breast cancer, two large series, both in newly diagnosed or early stage breast cancer, support a correlation between immune gene signature and better clinical outcomes. Immune infiltrates and prognosis in breast cancer IHC analysis of tissue microarrays derived from 179 treatment-nave breast tumors revealed that high levels of macrophages and CD4+ T cells correlated with reduced overall survival (OS), while high levels of CD8+ T cells combined with low levels of macrophages and CD4+ T cells correlated with increased OS.

Intratumoral B cells and immunoglobulin C have similar predictive and prognostic value in breast cancer which are associated with favorable prognosis in breast cancer. Patients with TNBC with at least 50% TILs (10.5% of patients) had a 5-year disease-free survival of 89% compared with 62% (p = 0.018). Multivariate analysis indicated that amongst all breast cancer subtypes, only core basal TNBC demonstrated a significant correlation between intratumoral CD8 staining and favorable prognosis. The B-cell metagene has also been associated with good outcome in TNBC.

Accumulating data now suggest that certain chemotherapeutic drugs, such as anthracyclines, mediate their anticancer activity not only by direct cytotoxic effects but also through activation of CD8+ T-cell responses. Immunotherapeutic opportunities for triple . negative breast cancer Compared with other subtypes, the outcome of TNBC has been shown to be particularly influenced by tumor-infiltrating lymphocytes. Therefore, different immunotherapeutic strategies, aiming at blocking or activating specific targets, are currently envisaged.

One of the most promising approaches consists of the use of antagonists against inhibitory receptors that become upregulated on antitumor T cells, such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3). PD-L1 and IDO (indoleamine 2,3-dioxygenase), expressed on dendritic cells and tumor cells, Immunosuppressive cytokines [such as interleukin (IL)-10, IL-23, transforming growth factor (TGF), adenosine, prostaglandin E2 (PGE2), vascular endothelial growth factor A (VEGF-A)]

Immunosuppressive enzymes (such as CD73 and arginase I), could also be targeted to stimulate antitumor immune responses. Alternatively, some approaches aim to activate specific immune targets, such as the coreceptors CD137 (41BB) and OX40, expressed on T cells. Finally, recent evidence suggests that specific tumor antigens, such as MUC-1 and NY-ESO-1, may constitute targetable vaccine antigens.

The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells specific for these tumor antigens is also envisaged. Immune checkpoint blockade In humans with cancer, antitumor immunity is often ineffective due to the tight regulation associated with the maintenance of immune homeostasis. One of the major limitations is a process known as T-cell exhaustion, which results from chronic exposure to antigens and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions. Blocking of one or several of these immune checkpoints with monoclonal antibodies (mAbs) has been shown to rescue otherwise

exhausted antitumor T cells, and most importantly, has been associated with objective clinical responses in cancer patients. The first immune-checkpoint inhibitor to be tested in a clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) mAb. Anti-CTLA-4 mAb therapy enhances the antitumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells PD-1 is another inhibitory coreceptor expressed on activated and exhausted T

cells. Its ligand, PD-L1, is often found overexpressed in various types of cancer. Administration of blocking antiPD-1/anti-PD-L1 mAbs enhance adaptive antitumor immune responses by preventing T-cell exhaustion. Two phase I trials recently reported clinical responses with anti-PD-1 or anti-PDL1 mAb in pretreated patients with diverse tumor types. Agonistic of tumor necrosis factor receptor superfamily Members of the TNF receptor superfamily also play an important role as regulators of T-cell function. Activation of these costimulatory receptors may further enhance the generation of tumor-reactive T cells in the context of cancer therapy. Costimulatory receptors of the TNF receptor family are composed of OX40 (CD134), 4-1BB (CD137),

CD27, CD30, and herpes virus entry mediator. When activated, each of these receptors can enhance cytokine production and T-cell proliferation in response to T-cell receptor signaling. Blocking the immunosuppressors Targeting immunosuppression by soluble mediators is another attractive approach for cancer immunotherapy. A plethora of immunosuppressive factors has been associated with tumorigenesis, including TGF, indoleamine 2,3-dioxygenase (IDO), arginase, prostaglandin E2, and extracellular adenosine.

In support of this model, mice genetically deficient in IL-23 are significantly protected against a wide range of malignancies and mice treated with a blocking antibody against IL-23 have a decreased risk of tumor formation and a faster elimination of transplanted tumor cells. Conclusion Unlike other molecular subtypes of breast cancers, triple-negative disease does not benefit from targeted therapies and is associated with worse clinical outcomes. As such, TNBC remains a challenge in medical practice. Among the new therapeutic options for TNBC, cellular or molecular immunotherapies appear to be very promising approaches. Their rational has been supported by several studies showing that TNBC outcome is correlated with tumor-immune infiltrate.

Building on these results, a variety of different immunotherapeutic strategies are currently being tested in preclinical and clinical studies, with some showing promising therapeutic activity. Among them, the use of immune-checkpoint blocking antibodies, such as anti-PD-1 or antiPD-L1, is particularly attractive. Conclusion Importantly, immune-stimulating therapies might act synergistically when combined with chemotherapeutic drugs currently used in the clinic. As we have discussed, other immune-based strategies that might be promising for TNBC include the adoptive transfer of CARengineered T cells or the development of tumor vaccines against CT antigens, which appear highly expressed in TNBC.

Towards new therapeutic approaches, one should keep in mind that TNBC itself is a highly heterogeneous disease, implying that not all patients will benefit from given immunotherapeutic strategies. The next challenge will be to find the optimal clinical setting for each new treatment. Thank you

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