6.1.3　Application of LAK

LAK cell therapy is a technique whereby the lymphocyte count is increased in an in vitro environment with interleukin (IL)-2, and it has become the basis of numerous immunotherapy assays that are currently in use [36].

LAK cells are used in adoptive immunotherapy for the treatment of malignant diseases.The therapy involves the removal of peripheral blood from a patient, depletion of red blood cells from the blood to produce a lymphocyte-containing white blood cell fraction, incubating the blood fraction in culture medium with interleukin-2 (IL-2) to induce their transformation into tumor-destroying LAK cells, and injecting the LAK cells into the patient along with interleukin-2.LAK cells are thought to be similar to NK cells in that they lyse target cells in a nonmajor histocompatibility complex (MHC)-restricted manner [36].(https://www.daowen.com)

As with NK cells, there is evidence that DCs can reciprocally activate LAKs in vitro.A recent murine study has also shown that co-injection of LAKs and DCs into tumors led to regression associated with protection against secondary re-challenge.These data suggest that combination LAK/DC therapy holds promise as a treatment for cancer, based on the hypothesis that DC-activated LAKs will effectively kill tumour targets to liberate TAAs for uptake by DCs within an inflammatory tumour microenvironment.The TAA-loaded mature DCs will then migrate to secondary lymphoid tissue and present TAAs to resident T cells for priming of an additional adaptive antigen-specific response.Moreover, activation of LAKs by co-administered DCs may remove the need for IL-2 and hence reduce the toxicity associated with LAK therapy in the past.This preclinical study investigated the interaction between clinically relevant LAKs and DCs,their ability to reciprocally activate each other, and the potential of the LAK/DC combination to prime both innate and adaptive immune responses against melanoma in human in vitro priming assays.We show that DCs are effectively matured by LAKs, while maintaining their phagocytic function for effective uptake of potential TAAs.In parallel, LAK cytotoxicity is enhanced by co-culture with DCs, as is secretion of inflammatory IFN-γ and TNF-α.Furthermore, the addition of LAKs to tumor cell co-cultures with DCs increases specific CTL priming.Hence, LAKs/DCs have potential as a combination cell immunotherapy for priming of both innate and adaptive anti-tumor immunity [36].

Coculture of LAK cells with DC (LAKDC) has been reported to eliminate the need for coadministration of IL-2, due to bi-directional signaling supporting LAK cell activation and viability, as well as inducing DC maturation and the production of pro-inflammatory cytokines.In vivo studies have shown that the combination of LAKDC can effectively eradicate subcutaneous tumors, leading to the generation of antitumor immunity, whereas treatment with either cell type alone was ineffective.27 Previous studies have also highlighted DC as effective cell carriers for reovirus in the presence of neutralizing serum for the treatment of melanoma.DC protected reovirus from antibody neutralization by internalization of viral particles, making reovirus unavailable for NAb binding.The use of DC in combination with LAK cells may, therefore,provide effective cell carriage for reovirus, leading to antitumor responses mediated by direct cytotoxicity and=or the generation of antitumor immunity [36].