Review: Adoptive immunotherapy against ovarian cancer

Adoptive cell transfer (ACT) is the transfer of cells into a patient.^[1] The cells may have originated from the patient him- or herself and then been altered before being transferred back, or, they may have come from another individual. The cells are most commonly derived from the immune system, with the goal of transferring improved immune functionality and characteristics along with the cells back to the patient.


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Published: 17 May 2016

Tumor infiltrating Lymphocytes (TIL)

 Clinical activity of TILs

Ongoing clinical studies

NK cells and LAK cells

CIK cells

Clinical activity of NK, LAK and CIK cells agains ovarian cancer

Conclusions

Adoptive cell-therapy has been shown to be an active treatment for different kinds of cancers, such as melanoma and other solid and hematological malignancies [31, 60, 61, 66, 72, 73]. The demonstration that the presence of inflammatory infiltrate correlates with a better prognosis for patients with EOC, suggests that it may be a relevant tool also in the treatment of EOC [6].

Results of several preclinical studies indicate that both HLA unrestricted immune effectors and HLA restricted T-lymphocytes have a cytotoxic activity against EOC cells in vitro [46, 64].

However, clinical research is still at an early stage and only few evidences of efficacy of adoptive immunotherapy in EOC have been reported, in particular regarding the addition of a maintenance therapy with CIK or TIL to front line standard treatments. This additional therapy seems to be able to improve clinical outcome prolonging PFS and OS in patients with a newly diagnosed EOC [42, 55]. On the contrary, the few published clinical trials with NK in other clinical settings such as multi-resistant EOC, were not able to demonstrate any activity of adoptive immunotherapy.

An Important issue that may significantly influence the outcome of clinical ACT is the employment of preparative lymphodepleting regimens. The scope of such treatments is to eliminate potentially immune-suppressive elements and create an appropriate “immunologic space” for the incoming immune effectors, reducing their competition for sustaining cytokines. Currently, there is no agreement on what may be the optimal lymphodepleting regimen. Combinations of Cyclofosfamide, Fludarabine and low dose total body irradiaton (TBI) seem to provide the best results and are therefore explored in clinical trials [23, 28].

The definition of the most suitables T cell subtypes for ACT is current object of intense research efforts; differentiation state of CD8+ T cells is inversely related to their capacity to proliferate and persist. These findings may be clinically relevant, and younger T cells are statistically positively correlated with clinical effectiveness in ACT trials [23, 28].

One of the possible limits to the clinical employment of adoptive immunotherapy is represented by the complexity of the procedures involved in this kind of treatments.

Cell therapy must be individualized, because the therapeutic agent is represented by patient's own cells which have to be collected, expanded and finally re-infused, with every step performed in GMP (Good manufacturing practice) validated facilities according to rigorous and stringent regulations. Personalization of adoptive cell-therapy, however, can represent an advantage: each tumour has different biological and molecular features and immunotherapies based on the use of autologous cells, have potential of high specificity, not achievable with chemotherapy.

Adoptive immunotherapy seems to be generally well-tolerated and toxicities reported are especially related to use of cytokines (such as IL-2) to promote cellular expansion.

Other important potential toxicities associated with ACT may be due to undesired antigen-recognition in healthy organs or to massive cytokine storm even if such events appear more likely to occur with genetically redirected lymphocytes [74].

Furthermore, the systemic administration of IL-2 might induce an undesired in vivo expansion of T regulatory cells (Treg) that may counteract the beneficial effect of ACT [23].

In melanoma, the presence of TILs was shown to be functionally linked to clinical benefit obtained with checkpoint inhibitors such as antibodies blocking CTLA-4 and PD1 molecules [75, 76, 77]. Preclinical evidence on the importance of PD-1 expression in Tumor-infiltrating NY-ESO-1-specific CD8+ T cells is also available [78]. In relapsed resistant/refractory ovarian cancer anti PD-1/PD-L1 antibodies have shown promising activity with favourable safety profile [79, 80].

On these bases, adoptive immunotherapy may potentially synergize with checkpoint inhibitors treatments. This future perspective may be even more applicable with genetically redirected T lymphocytes as supported by encouraging preclinical evidence [81, 82].

NK seems to be related to more severe toxicities, the only clinical trial published, investigating NK efficacy in patients with multi-resistant EOC reported a death for tumor lysis syndrome, two cases of passenger lymphocyte syndrome, an autoimmune haemolytic anaemia and no improvement of clinical outcome [67]. Although the prognostic role of NK cells infiltration is still controversial, with published article that suggest their negative prognostic role [83].

In conclusion, application of adoptive cell therapy against EOC appears as a promising perspective, not yet sufficiently supported by convincing clinical data. It seem reasonable that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. These concepts should be incorporated and integrated in the multidisciplinary therapeutic strategy of ovarian cancer [84].

The complexity and costs required to explore clinical applications of these approaches remain open issues that may be faced if supported by further and stronger preclinical evidences.

Further studies are therefore needed to better define the patterns involved in the immune response to EOC and the escape mechanisms allowing neoplastic cells survival and proliferation, in order to develop strategies to make adoptive immunotherapy clinically effective.