Adoptive Immunotherapy with antitumor 41 Immune cells

Passive immunotherapy with large doses of activated antitumor lymphocytes was also employed since there was a possibility that active immunization would be insufficient to induce enough of an immune response to cause tumor regression in the immunosuppressed patient with a large tumor burden. Adoptive transfer of tumor-reactive T cells cultured from tumor-infiltrating lymphocytes, along with IL-2, resulted in a clinical response in melanoma patients.65 Adoptive transfer of EBV-specific T cells resulted in regression of EBV-associated lymphoma. Intraportal infusion of in vitro MUCl-stimulated T cells was performed in pancreatic cancer, yielding preliminary results that indicate inhibition of liver metastasis. Although the clinical use of tumor-reactive T cells was previously limited due to the difficulty in generating tumor-reactive T cells for most cancers, it is now possible to generate these cells from the PBMC of cancer patients by in vitro stimulation, using the identified tumor antigens.66 Tumor-reactive T cells from patients preimmunized with tumor antigens were generated more efficiently, which suggests that combined use of active and passive immunotherapies is ideal. One of the problems that arises from adoptive transfer of cultured T cells is the low efficiency of administered T cells in in vivo maintenance and accumulation in tumor tissues. However, it was recently reported that nonmyeloablative, lymphodepletive pre-treatment with cyclophosphamide and fludarabine resulted in extended persistence of administered tumor-reactive T cells in peripheral blood and tumor tissues and increased tumor regression, which may be due to suppression of patient immune responses or the need to make room for homeostatic proliferation of transferred lymphocytes.67 Adoptive immunotherapy with IL- 2-activated PBMC, LAK (lymphokine activated killer) cells displayed some antitumor effects when locally administered (ie, by intrapleural or intraarterial infusion) for lung or liver cancer. Intraportal administration following intraoperative irradiation in pancreatic cancer patients is reported to result in possible prolongation of survival68.

Adoptive immunotherapy involves harvesting the patient's peripheral blood T-lymphocytes, stimulating and expanding the autologous tumour-reactive T-cells using IL-2 and CD3-specific antibody, before subsequently transferring them back into the patient. Twelve patients with advanced pancreatic cancer who underwent resection, intraoperative radiotherapy and intraportal infusion of LAK cells with recombinant IL-2 had lower incidence of liver metastasis compared to controls (three of 12 vs ten of 15; p<0.05)69. There was no significant difference in overall survival, but more patients were alive three years later (36% vs none).

Telomerase —Telomerase is a reverse transcriptase that contains a RNA template used to synthesise telomeric repeats onto chromosomal ends. Activation of telomerase and its maintenance of telomeres play a role in immortalisation of human cancer cells, as telomeres shrink after each cell division 70. Telomerase activity is found in 92-95% of pancreatic cancers 71-72, and is associated with increased potential of invasion and metastasis and poor prognosis 73-74. Upregulation of telomerase may also be responsible for the development of chemotherapy resistance 75. Adenovirus-mediated transduction of p53 gene inhibited telomerase activity in MIAPaCa-2, SUIT-2 and AsPC-1 cells, independent of its effect on apoptosis, cell growth and cycle arrest 76. Antisense to the RNA component of telomerase seemed to increase susceptibility of Panc-1 cells to cisplatin 77. Telomerase reverse transcriptase antisense oligonucleotide (hTERT-ASO) was found to inhibit the proliferation of BxPC-3 cells in vitro by decreasing telomerase activity and increasing apoptosis 78. Adoptive transfer of telomerase-specific T-cells was studied in a syngeneic pancreatic tumour mouse model 79. T-cells were produced in vitro by coculturing human lymphocytes with telomerase peptide-pulsed dendritic cells (DCs) or in vivo by injection of peptide with adjuvant into C57BL/6 mice. Animals treated with these T-cells showed significantly delayed disease progression.

MUC1 —Adoptive transfer of MUC1-specific cytotoxic T-lymphocytes (CTLs) was able to completely eradicate MUC1-expressing tumours in mice 80. Intraportal infusion of In vitro MUC1-stimulated T-cells was performed in patients with pancreatic cancer, with subsequent inhibition of liver metastasis 81. In a study of eleven patients with lung metastases (from colorectal, pancreatic, breast, lung, or melanoma primaries), effector cells were generated in vitro using cultured DCs, synthetic peptide, peripheral blood lymphocytes, IL-2 and anti-CD3 antibody 82. A partial response of the lung metastases was observed in a patient with pancreatic cancer who received these cells stimulated with MUC1.

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