Chemokines are small cytokines often found to be involved in cancer progression, Particularly, the C-C chemokine motif ligand 2/C-C chemokine receptor 2 (CCL2/CCR2) pathway has been shown to drive a pro-inflammatory microenvironment which favors tumor progression
[49][94]. The following study evaluated the safety profile and potential efficacy of a CCL2 inhibitor, propagermanium (PG), as an antimetastatic drug in perioperative patients with primary breast cancer. Overall, a low-grade adverse event profile was reported. IL-6 levels were reduced in a dose-dependent manner which, given the fact that IL-6 is implicated in the metastatic dissemination of breast cancer
[50][95], suggests that PG may have the ability to hinder metastasis in human BC.
6. Adoptive Cell Therapies (ACTs)
6.1. Tumor-Infiltrating Lymphocyte (TIL) Therapy
.1. Tumor-Infiltrating Lymphocyte (TIL) Therapy
TIL therapy often involves the ex vivo expansion of either CD8+ or CD4+ T cells and their infusion back into the patient
[51][100]. Both allogeneic and autologous transplants have been attempted for breast cancer patients in the past with each approach having its own harms and benefits. For example, allogeneic transplants exhibited significant toxicity whereas autologous transplants were less efficacious compared to allogeneic
[52][53][54][55][102,103,104,105]. TIL therapy has been found to be most effective in patients with a high somatic mutational burden as it allows for the expansion of TILs specifically against tumor-specific neoantigens. For example, a case study for a 49-year-old patient diagnosed with ER-positive metastatic breast cancer reported disease regression following a combination of TIL therapy, specifically against proteins mutated in that patient, IL-2 cytokine therapy and PD-1 immune checkpoint inhibition
[56][106].
6.2. Engineered TCR Therapy
Engineered TCR therapy describes the genetic engineering of the TCR of a patient’s own T cells to specifically recognize tumor antigens
[57][113]. Most αβTCR-engineered cells can only be used against antigens presented by MHC molecules expressed on immune cells such as dendritic cells
[58][99]. For instance, Qiongshu et al. (2018) successfully engineered CD8+ T cells to specifically recognize PLAC1 in different breast cancer cell lines. PLAC1 is an example of an antigen known to be often expressed in breast cancer
[59][114].
6.3. Chimeric Antigen Receptor (CAR) T Cell Therapy
Chimeric antigen receptor (CAR) therapy includes the genetic modification of a patient’s own T cells that involves the addition of a CAR gene. The latter encodes for a receptor that specifically recognizes certain cancer antigens. This allows for a robust and potent anti-tumor response
[60][61][107,120]. For example, the success of the anti-CD19 CAR T cell therapy against B cell lymphoma leading to its FDA approval is well known
[62][63][64][65][121,122,123,124].
On the contrary, CAR T cell therapy has not been as successful in solid malignancies such as breast cancer mainly because of the presence of an immunosuppressive tumor microenvironment as opposed to haematological malignancies where there is none. An important factor to consider is choosing an appropriate target antigen that is highly expressed in tumor cells but not so much in healthy tissue
[66][133].
Overall, several other antigens have been identified so far that appear to be promising targets for the generation of such CAR T cells such as
[67][68][69][142,143,144]. For example, receptor tyrosine kinases (RTKs) drive the activation of several signaling pathways such as the PI3K, MAPK or JAK/STAT pathways, leading to numerous cellular processes such as proliferation, differentiation and apoptosis
[70][71][145,146]. RTKs identified in breast cancer as promising candidates for CAR cells include HER-2, EGFR and ROR1
[69][72][73][74][75][76][77][78][79][144,147,148,149,150,151,152,153,154]. Cell surface antigens present on tumor cells are another possible candidate for CAR cells. For instance, MUC1 upregulation was detected in the majority of breast cancer subtypes and promotes the metastatic dissemination of tumor cells through the activation of ERK1/2 and NF-kB pathways
[68][69][70][143,144,145].
7. Limitations
7.1. Immune Checkpoint Inhibitors (ICIs)
Despite the worldwide implementation of ICIs in clinical practice, there are multiple challenges which must be taken into consideration. Firstly, predictors of response are considered the most important challenge among physicians, especially in the case of non-small-cell lung cancer (NSCLC), since only 30–40% of patients seem to benefit from ICIs
[73][74][148,149]. Up to date, there are gaps in clinical evidence for concurrent administration of steroids and ICIs. Retrospective studies showed that patients taking steroids had a lower progression-free survival or overall survival
[75][76][77][78][79][150,151,152,153,154] but were not negatively affected while taking steroids for managing side effects
[80][155]. It remains unclear if steroids reduce the efficacy of ICIs or if there is an eventual difference driven by a more aggressive form of disease. ICI-induced adverse effects, also known as immune-related adverse effects (irAEs), are more prevalent in organs such as the skin, lungs, liver, kidneys, gastrointestinal and nervous system. ICIs have been associated with gastrointestinal and hepatic adverse events, with colitis being the most common side effect. According to comprehensive systematic review by Wang et al., the majority of deaths were attributed to colitis (70%) with anti-CTLA-4 therapy and pneumonitis and hepatitis (22%) with anti-PD-1/PD-L1-therapy. With combination PD-1/CTLA-4 therapy, deaths were frequently due to colitis (37%) and myocarditis (25%)
[81][156]. The median time of onset of neurological adverse events (nAEs) was 6 weeks after ICIs treatment initiation. The incidence of severe nAEs (grade 3 and 4) with anti-CTLA4 therapy was slightly higher (0.7%) than with anti-PD1 therapy (0.4%)
[82][157]. The incidence of ICI-induced liver dysfunction is much lower compared to diarrhoea and is reported in about 1–6% of patients, mostly at grades 1 and 2
[83][84][158,159]. The greater incidence and severity of irAEs with anti-CTLA-4 therapy compared to ani-PD-1/PD-L1 therapies reflects the potentially more dominant role of CTLA-4 compared to PD-1 as a negative T-cell regulator. It is worth mentioning that irAEs of combination ICIs are more severe than those of monotherapy
[85][160]. Combination ICIs have been associated with endocrinopathies such as thyroid disorders and hypophysitis, which can be life-threatening if not recognized early
[86][161].
To tackle the aforementioned challenges, microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) could be implemented, as it correlates with stronger responses with ICIs. In fact, it has already found application in as many as 24 cancer types with the highest percentage of MSI-H in endometrial cancer (17%), gastric adenocarcinoma (9%), small intestinal malignancies (8%), colorectal adenocarcinoma (6%) and lower for breast carcinoma (0.6%)
[87][162]. The management of grade 1–2 hepatic dysfunction generally involves close monitoring with liver tests to avoid grade 3–4 liver toxicity. The management of grade 3–4 hepatic dysfunction requires high dose intravenous glucocorticoids for 24–48 h, followed by an oral steroid over at least a period of 30 days
[84][159]. Regarding neurological AEs, no standard treatment has yet been defined. Clinical improvements have only been reported after the ICI treatment discontinuation
[85][160].
7.2. Breast Cancer Vaccines
BC vaccines present with good tolerance but without significant clinical benefit. Particularly, the Theratope
® (STn) vaccine for metastatic BC and the NeuVax™ [Nelipepimut-S (NPS), or E75] vaccine for adjuvant BC both failed to display clinical benefit during phase 3 studies
[88][89][163,164].
7.3. Cytokine Therapies
Just like with every treatment, cytokine therapy has its own limitation—not particularly specific for breast cancer. The major challenges presented here originate from the core principles of cytokines. First of all, being pleiotropic makes their targeting not specific to the TME; thus, off-target effects often occur. Additionally, due to the fact that different cytokines can regulate the same pathways, blocking one of them may not be enough as the others can compensate for that loss. Finally, due to their ability to regulate the immune system of the host, a blockade of any cytokines can lead to impairment of the immune system and can lead to autoimmunity or tissue damage
[90][169]. The introduction of point mutations or fusion with their receptor counterparts is a way of overcoming the broad specificity of cytokines
[91][170]. For example, IL-2 can activate both T cells and NKs but regulatory T cells (Tregs) as well. The latter lead to immunosuppression whereas the former to activation of the immune system
[92][171]. Several studies have used site-directed mutagenesis to reduce the affinity of IL-2 for the receptor on Tregs. Overall, these mutants have shown comparable activity to their wild-type forms and enhanced efficacy in in vivo settings
[93][94][95][172,173,174].
7.4. Adoptive Cellular Therapies (ACTs)
Each type of ACT from TIL to CAR T cell therapy has its own disadvantages as well. Some patients have non-functional T cells or even no T cells at all as they have what is known as a “cold” tumor (i.e., not immunogenic)
[96][97][180,181] and therefore must be further modified to be applied in those patients. For example, they must either be co-cultured with IL-2 to further expand and activate the cells or select T cells that are tumor-specific
[98][182].
8. Conclusions
Immunotherapy has revolutionized the treatment of breast cancer, significantly improving the curative effect when added to standard therapies. Despite challenges, immunotherapy remains a promising therapeutic strategy and ongoing trials will confirm its clinical benefit in combination with conventional therapies. Further knowledge about the immunosuppressive tumor microenvironment could aid the selection of patients who are most likely to respond to the aforementioned regimens.