Immunotherapy in Breast cancer: A Review of literature

Pratik Patil^1*, Veda Padma Priya², Ranga Rao Ranga Raju², Waseem Abbas² and Shubha Garg^2
*Correspondence: Pratik Patil, Department in Medical Oncology, Max Super-Specialty Hospital, Shalimar Bagh, New Delhi, India, Tel: 09637439163, Email:

Keywords

Cancer • Breast cancer • Immunotherapy • RNA

Introduction

The basis for immunotherapy in cancer has revolved around the concept of immunogenicity. For a long time, breast cancer has been considered no immunogenic. However, the role of the immune system in the emergence of breast cancer has been firmly established [1-3]. Random or inherited genetic and epigenetic abnormalities confer proliferative and/or survival advantages on certain cells. By targeting the new antigens created by these genetic changes, the immune system plays a central role in cancer control that can be host-protective or tumor promoting [4].

Traditional pathology and immunohistochemistry, gene expression profiling, RNA sequencing, and combined scores have been used to assess the immunogenicity of breast cancer. Traditional pathology tools allow the assessment of breast cancer immunogenicity by studying the presence of Tumor-Infiltrating Lymphocytes (TILs) and assessing their types and correlation with survival and recurrence. While TILs were not found to have a prognostic value in the overall breast cancer population or ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) patients, TILs were found to have a prognostic value for Disease-Free Survival (DFS) and Overall Survival (OS) in TNBC [2,5]. In patients with TNBC who had residual disease after neo-adjuvant chemotherapy, the presence of TILs was found to be associated with better OS as well as with metastasis-free survival. In ER-negative breast cancers, TILs, specifically CD8+ lymphocytes, were associated with better breast cancer-specific survival [5,6]. The presence of CD8+ lymphocytes in patients with ER-negative breast cancers was also related to longer DFS [6].

Immunogenicity of a tumor is evaluated by the assessment of its antigenicity and the latter is evaluated by assessing its mutagenicity. TNBC has the highest mutational load compared with HR-positive breast cancers and high mutational load is associated with better prognosis in TNBC and HER2+ compared with low mutational load in the same type of breast cancer [7,8].

Review of Literature

Several strategies have been used to harness the power of the immune system and redirect it to eradicate breast cancer or to induce immune dormancy like Breast cancer vaccines, Monoclonal Antibodies (MAbs), Antibody-Drug Conjugates (ADCs), Checkpoint inhibitors, Stimulatory molecule agonist antibodies, Combination immunotherapy trials.

Monoclonal antibodies are an integral part of our armamentarium in the fight against cancer. They can be divided into those that target the immune system (checkpoint inhibitors) and those that target oncogenic membrane receptors (HER2) or other surface molecules of unknown function (CD20). Trastuzumab is a standard component of the treatment of HER2-positive breast cancer. Its development in the 1990s was considered a landmark achievement in the field of targeted therapy [9]. The failure of TKIs to make a significant difference in the outcomes of patients suggests that blocking the oncogenic stimulation of HER2 might not be the main mechanism of action of HER2-targeting MAbs. The Finer investigators found that every 10% increase in TILs was associated with decreased distant recurrence and other studies found that TILs had a prognostic and predictive value as their presence predicted for higher pCR to Trastuzumab-containing chemotherapy and better DFS [4,10]. A meta-analysis of neo adjuvant RCTs showed that the pCR rate was significantly higher in patients with lymphocyte-predominant breast cancer in HER2-positive breast cancer settings, with an absolute difference of 33.3% (95% CI=23.6%-42.7%) [11].

TDM1 or ado-Trastuzumab emtansine is now FDA approved for patients with HER2-positive MBC whose disease has progressed on trastuzumab and a taxane based on the results of the EMILIA (Emtansine versus Capecitabine plus Lapatinib in patients with previously treated HER2-positive advanced breast cancer) trial [12]. Despite the success of TDM1 in HER2-positive breast cancer, 50% of the patients did not respond on the EMILIA trial. To meet the need of those patients, other ADCs targeting HER2 are being investigated. Three ADCs targeting HER2 are using Trastuzumab, DS-8201a (drug/target: Exatecan/Topoisomerase I), SYD985 (drug/target: Duocarmycin/DNA), and ADCT-502 (drug/target: Pyrrolobenzodiazepine dimer/DNA). The other ADCs targeting HER2 are using different MAbs and different drugs and targets.102 Three ADCs are being developed for TNBC [13].

Targeting programmed death-1 and programmed death-ligand 1 (PD-1/ PD-L1) in breast cancer appears increasingly appealing after the success of such an approach in other cancers. The PD-1 receptor inhibits innate and adaptive immunity when upregulated on immune cells and engaged by its ligand, PD-L1 [14]. Currently, results from a phase Ib study in heavily pretreated patients with TNBC who received Pembrolizumab demonstrated an acceptable toxicity and good safety profile [15]. The Keynote-086 trial is a phase II study with Pembrolizumab in patients with metastatic TNBC as first-line (cohort B; n=52; 100% were positive for PD-L1 expression) and subsequent line therapies (cohort A; n=170; 60% were positive for PD-L1 expression) [15]. Overall response rate (ORR) was 4.7% in cohort A and 23% 02 August ,2021; in cohort B. The 1- and 2-year OS rates were 37% and 18% in cohort A and 63% and 47% in cohort B, respectively. Similar results for ORR were obtained using single-agent Atezolizumab in frontline (first line 23%) and subsequent line settings (second line 4% and third line 8%) (Table 1).

CTLA-4 is another immune checkpoint that is being targeted in breast cancer. Similar to the PD-1/PD-L1 inhibitors, most ongoing clinical trials involving CTLA-4 generally revolve around melanoma. Ipilimumab Is a CTLA- 4 MAb FDA approved for the treatment of unrespectable melanoma. It is currently being used in a phase I study examining its safety in combination with a new anti-B7-H3 mAb, Enoblituzumab, to patients with multiple refractory cancers, including TNBC. Ipilimumab Is also being combined with Entinostat and Nivolumab in a phase I study for metastatic HER2-negative breast cancer as well as with just Nivolumab in a phase II studies for patients with recurrent stage IV HER2-negative breast cancer. There are other ongoing trials evaluating the combination of a CTLA-4 inhibitor, with additional treatments [11]. There is a phase II study of Tremelimumab (CTLA-4 inhibitor) with a PDL1 inhibitor, MEDI4736, in patients with HER2-negative breast cancer to look for the safety and efficacy of this regimen. A phase I study has already been completed with the combination of Tremelimumab and Exemestane in patients with hormone-responsive advanced breast cancer.

The PD-1 MAbs (Nivolumab and Pembrolizumab) and PD-L1 MAbs (Atezolizumab, Durvalumab, and Avelumab) are being tested in many combination clinical trials. Some trials are exploring combinations with chemotherapy and others with biological agents targeting HER2-positive or hormone receptor-positive breast cancers. However, most of these studies are designed for TNBC due to its known immunogenicity and results from singleagent checkpoint inhibitors that showed efficacy in this subtype [8].

Traditionally, the effect of chemotherapy has been explained by the induction of apoptosis of cancer cells after interrupting their cell cycle apparatus. However, alternative mechanisms involving the immune system have been recently invoked. Taxanes, doxorubicin, and Cyclophosphamide, which are standard chemotherapeutic agents in the treatment of breast cancer, are known to have major effects on the immune system in animals and human experiments. For example, Taxanes, as a class, increase serum IFN-γ, IL-2, IL-6, and GM-CSF levels as well as reducing the levels of IL-1 and TNF-γ. Paclitaxel given neoadjuvant increases the levels of TILs within the tumor itself (Table 2).

The immune effects of chemotherapy may be summarized by rendering dying cancer cells more visible to the immune system by exposing their TAAs, stimulating the innate immune system, stimulating T-cell differentiation, promoting a cytokine profile that increases the likelihood of TH1 polarization, inhibition of MDSCs and M2 macrophages, and suppression of FOXP3+ Treg cells. Acknowledging these mechanisms is of major importance to optimize their benefit and minimize toxicity to the immune system that becomes an important executioner of chemotherapy effect [2,9].

The overall goal of cancer immunotherapy is the activation of the immune system against the cancer. Vaccination has traditionally been to boost the latent immune response to tumour-specific antigens. Approaches have included cellbased protocols involving immunization with whole autologous or allogeneic tumours, as well as antigen-based strategies involving immunization with proteins or peptides overexpressed in tumours and under expressed in normal tissues. HER2 and MUC1 are the predominant antigens used in human breast cancer vaccine trials. Although vaccination using these antigens may demonstrate tumour-reducing effects, neither antigen provides any tissue or tumour specificity because both are expressed in a variety of normal tissues and tumours raising concerns about the possibility of off target damage if a robust immune response is developed.

Discussion

However, despite the lack of inherent tissue specificity of HER2 and MUC1, these concerns about systemic autoimmune sequelae have not been substantiated so far. Tumour-associated carbohydrate antigens are pan-immunogens that elicit responses to several antigens, thus achieving the same goal as a multivalent vaccine. To overcome their low immunogenicity, investigators have used CMPs that seem to elicit a broad-spectrum antitumor reactivity. Here again, the activation of immune responses against TACAs raises concerns regarding the balance between “tumour destruction” and “tissue damage,” as TACAs are also expressed on normal tissues. The evidence gleaned from phase I and II trials is reassuring. It is not clear which subtype of breast cancer would benefit from this approach.

Monoclonal antibodies are an integral part of our armamentarium in the fight against cancer. They can be divided into those that target the immune system and those that target oncogenic membrane receptors (HER2) or other surface molecules of unknown function (CD20). Anti-HER2 antibodies have changed the outlook of this disease. The failure of small molecules that inhibit the oncogenic stimulation of HER2 and the lack or minimal response to these antibodies in tumours that lack TILs suggest that their action is more immune mediated than oncogenic mediated.

Monoclonal antibodies that inhibit checkpoints (checkpoint inhibitors) are changing the paradigm of care in many solid tumours. The first results of their use in breast cancer suggest that they are the most effective in TNBC. Their use is being investigated in the other subtypes. Due to the low immunogenicity of luminal A and B breast cancers, a combination strategy using vaccines to stimulate the immune response followed by checkpoint inhibitors is rational but its clinical usefulness remains to be proven.

Conclusion

Finally, the immune mechanism of chemotherapy is being increasingly recognized. Its contribution in the total effect of chemotherapy relative to the direct cytotoxic effect is not known. Any further development of chemotherapy in the future should take this aspect into consideration to maximize the immune stimulatory effect and minimize the immune suppressive effect of chemotherapy.

References

1. Malvia, Shreshtha, Sarangadhara Appala Raju Bagadi, Uma Dubey and Sunita Saxena. “Epidemiology of Breast Cancer in Indian Women: Breast Cancer Epidemiology.” Asia Pac J Clin Oncol 1 (2017): 13.
2. Liu, Shuzhen, Jonathan Lachapelle, Samuel Leung and Dongxia Gao, et al. “CD8+ Lymphocyte Infiltration is an Independent Favorable Prognostic Indicator in Basal-Like Breast Cancer.” Breast Cancer Res 14 (2012): R48.
3. Stanton, E Sasha, Sylvia Adams and Mary L Disis. “Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review.” JAMA Oncol 1 (2016): 1354-1360.
4. Kieber-Emmons, Thomas and Heinz Kohler. “Evolutionary Origin of Autoreactive Determinants (Autogens).” Proc Natl Acad Sci 83 (1986): 2521-2525.
5. Mao, Yan, Qu Qing, Xiaosong Chen and Ou Huang, et al. “The Prognostic Value of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Systematic Review and Meta-Analysis.” PloS One 11 (2016): e0152500.
6. Mahmoud, MA Sahar, Emma Claire Paish, Desmond G Powe and R Douglas Macmillan, et al. “Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer.” J Am Soc Clin Oncol 29 (2011): 1949-1955.
7. Vogelstein, Bert, Nickolas Papadopoulos, Victor E Velculescu and Shibin Zhou. “Cancer Genome Landscapes.” Science 339 (2013): 1546-1558.
8. Koboldt, C Daniel, Robert Fulton, Michael David Mclellan and Heather Schmidt, et al. “Comprehensive Molecular Portraits of Human Breast Tumours.” Nature 490 (2012): 61-70.
9. Cameron, David, Martine J Piccart-Gebhart, Richard D Gelber and Evandro De Azambuja, et al. “11 Years’ Follow-Up of Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Early Breast Cancer: Final Analysis of the Herceptin Adjuvant (HERA) Trial.” Lancet Lond Engl 389 (2017): 1195-1205.
10. Heppner, Barbara, Michael Untch, Carsten Denkert and Berit M Pfitzner, et al. “Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer.” J Am Assoc Cancer Res 22 (2016): 5747-5754.
11. Carbognin, Luisa, Pilotto Sara, Nortilli Rolando and Brunelli Matteo, et al. “Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes for Early Breast Cancer According to Disease Subtypes: Sensitivity Analysis of Randomized Trials in Adjuvant and Neoadjuvant Setting.” Oncologist 21 (2016): 283-291.
12. Diéras, Véronique, David Miles, Sunil Verma and Mark Pegram, et al. “Trastuzumab Emtansine versus Capecitabine plus Lapatinib in Patients with Previously Treated HER2-Positive Advanced Breast Cancer (EMILIA): A Descriptive Analysis of Final Overall Survival Results from a Randomized, Open-Label, and Phase 3 Trial.” Lancet Oncol 18 (2017): 732-742.
13. Trail, A Pamela, Gene M Dubowchik and Timothy B Lowinger. “Antibody Drug Conjugates for Treatment of Breast Cancer: Novel Targets and Diverse Approaches in ADC Design.” Pharmacol Ther 181 (2018): 126-142.
14. Yao, Sheng, Zhu Yuwen and Chen Lieping. “Advances in Targeting Cell Surface Signaling Molecules for Immune Modulation.” Nat Rev Drug Discov 12 (2013): 130-146.
15. Nanda, Rita, Laura Q M Chow, Dees E Claire and Raanan Berger, et al. “Pembrolizumab in Patients with Advanced Triple-Negative Breast Cancer: Phase Ib Keynote-012 Study.” J Am Soc Clin Oncol 34 (2016): 2460-2467.