Autolymphocyte therapy (ALT) is adoptive cellular therapy of cancer using ex vivo activation of autologous peripheral blood lymphocytes (PBL). Memory T cells are the principal effector population in ALT, with in vivo activity in patients with metastatic renal cell carcinoma (RCC) and melanoma, and ex vivo cytotoxicity against autologous tumor targets. However, the noncytolytic lymphocyte portion of ex vivo-activated memory T cells (ALT cells) may also contribute as antitumor effectors. Pretreatment of murine and human tumor cells ex vivo with chemotherapeutic agents can enhance their susceptibility to antitumor lymphocytes ex vivo and in vivo. To determine whether cis-diamminedichloroplatinum(II) (DDP) could enhance ex vivo antitumor effects of ALT cells by immunomodulation, human breast and colorectal carcinoma target cells were derived from both primary and metastatic surgical specimens and incubated in complete medium (CM) with DDP or in CM alone (control group). Viability of each group was confirmed by trypan blue-dye exclusion test. ALT cells were prepared from autologous PBL at surgery. Primary and metastatic tumor cells from each group were used as targets for ALT cells and levels of interferon-gamma (IFN-gamma) release were measured as a determination of antitumor effect and recognition. Primary tumor target cells incubated in DDP showed enhanced antitumor effects and recognition by autologous ALT cells, as measured by the IFN-gamma assay compared to non-DDP-treated controls. Metastatic autologous tumor target cells demonstrated less IFN-gamma release than did the primary targets, although this was enhanced by pre-treating metastatic tumor targets with DDP. ALT cells demonstrated minimal IFN-gamma release when incubated with allogeneic tumor targets. These data suggest that autotumor recognition of metastatic tumor targets is comparable to that of primary lesions following ex vivo pretreatment of metastatic cells with nonlethal doses of certain chemotherapeutic agents. DDP may somehow alter the physical properties of target cells, rendering them susceptible to immune-mediated attack and the combination of ALT and DDP may lead to increased therapeutic efficacy in patients with metastatic breast and colon cancer.

Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.

These data suggest that: (i) ex vivo activated memory T-cells are the principal component demonstrating significant tumour-specific cytotoxicity of ALT-cells against RCC tumour targets; (ii) CDDP may alter the physical properties of tumour cells rendering them susceptible to immune-mediated attack; (iii) the combination of ALT and CDDP may lead to increased therapeutic efficacy in patients with metastatic RCC.