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PubMed1991

Tumour rejection after adoptive transfer of line-10-immune spleen cells is mediated by two T cell subpopulations.

The growth of line-10 tumours in naive guinea pigs is prevented by adoptive transfer of spleen cells that are hyperimmune to this hepatocellular carcinoma. To study the T cell subpopulations responsible for the adoptive transfer of immunity, various cell populations were removed from immune spleen cells using monoclonal antibodies (mAbs) and magnetic microspheres. Spleen cell subpopulations were identified by mAb after flow cytometry and rosette formation with the magnetic microspheres. mAb CT5 was confirmed to be a pan T cell marker, while the CT6 (anti-T-suppressor/cytotoxic) and CT7 (anti-T-cell) markers were present on two different T cell subpopulations. So our results show that CT7 mAb cannot be used as a pan T cell marker as was published previously. Moreover, the mAb H155 (anti-T-helper/inducer) reacted with the same T cell subpopulation recognized by CT7. So we designated this H155/CT7-positive subpopulation as T helper/inducer cells. Removal of the CT6-, CT7-, or the H155-positive T cells from the immune spleen cells resulted in loss of the in vitro proliferative response to line-10 tumour protein and tuberculin purified protein derivative (PPD). The H155/CT7 (anti-T-helper/inducer)-positive spleen cells did not express MHC class II antigens as determined by mAb 25E3. In most experiments, elimination of MHC-class-II-positive cells did not change the in vitro proliferative response to line-10 protein, whereas the response to tuberculin PPD was completely abrogated. Immune spleen cells after depletion of CT6-, CT7- or H155-positive cells, failed to transfer immunity. However, after depletion of MHC-class-II-antigen-positive cells the line-10 immunity was still present, whereas the immune response to tuberculin PPD was lost. In conclusion, our data indicate that immunity to the line-10 tumour is the result of a cooperation between at least two different T cell subpopulations, the T helper/inducer (CT7/H155) cells and the T suppressor/cytotoxic cells (CT6). If this is a common feature, then the therapeutic approach of in vitro expanded TIL cells should take into consideration the requirement of two T cell subsets.

Animals↗
PubMed1990

Successful adoptive immunotherapy of minimal residual disease after chemoradiotherapy and transplantation of bone marrow purged of leukaemia with mafosfamide.

The effectiveness of adoptive immunotherapy in eliminating minimal residual disease in tumour-bearing mice after bone marrow transplantation was tested. This model mimics the human clinical condition when autologous bone marrow was purged ex vivo of leukaemia with mafosfamide or was not purged, and stored in liquid nitrogen before transplantation. Animals with minimal residual disease were prepared with marrow-ablative but leukaemia-noncurative doses of cyclophosphamide (CY) and total body irradiation followed by bone marrow transplantation. The next day after transplantation the recipients were injected with splenocytes immunized against the leukaemia cells (Imm-SPL) or monoclonal antibody (mAb). All the control mice died from leukaemia relapse, but 51% of purged bone marrow recipients, which received Imm-SPL, were cured. In similar conditions mAb did not exert a therapeutic effect. Imm-SPL were not able to eradicate minimal residual disease in the recipients of nonpurged bone marrow. Thus, in an animal model, we demonstrated that purging of bone marrow before grafting seems to be indispensable for successful adoptive immunotherapy of minimal residual disease (MRD) after autologous bone marrow transplantation.

Adjuvants, Immunologic↗
PubMed1997

Sensitizing T-lymphocytes for adoptive immunotherapy by vaccination with wild-type or cytokine gene-transduced melanoma.

BACKGROUND: For the relatively nonimmunogenic B16-F10 murine melanoma, it has been found that genetically engineered expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) but not interleukin (IL)-2, IL-4, or interferon-gamma (IFN-gamma) resulted in a vaccine that could induce resistance to rechallenge. Because T cells from lymph nodes draining the sites of some progressive tumors can mediate tumor regression after in vitro activation, it seemed possible that even apparently nonimmunogenic melanoma cells might induce similar preeffector cells in the vaccine-draining lymph nodes (DLNs). METHODS: C57BL/6 mice were vaccinated with B16-F10 cells that were either unmodified or genetically modified to produce IL-2, IL-4, GM-CSF, or IFN-gamma. DLNs were harvested 10 days after vaccination for adoptive immunotherapy (AIT). The DLN cells were activated with bryostatin 1 and ionomycin (B/I), expanded for 10 days in culture, and transferred to mice with 3-day pulmonary metastases. Pulmonary nodules were counted 14 days after AIT. RESULTS: Adoptive transfer of expanded DLN lymphocytes sensitized by inoculation of WT B16-F10, or IL-4, GM-CSF, or IFN-gamma expressing cells significantly reduced pulmonary metastases. Despite the spontaneous regression of IL-2-transduced B16-F10 tumors, DLN from mice inoculated with IL-2 producing B16 cells had little or no antitumor activity. CONCLUSIONS: B16-F10 vaccination strategies that apparently do not induce systemic immunity can effectively sensitize DLN preeffector cells.

Adjuvants, Immunologic↗
PubMed1996

Adoptive cellular immunotherapy of cancer in mice using allogeneic T-cells.

BACKGROUND: Adoptive cellular immunotherapy with autologous tumor-infiltrating lymphocytes (TILs) can induce tumor regression in patients with metastatic melanoma but requires both surgical tumor harvest and successful expansion of lymphocytes in vitro. In cases in which tumors are inaccessible or TILs fail to grow, the adoptive transfer of allogeneic TILs, haplotype matched for the restriction element for a common tumor antigen, represents a possible treatment alternative. Such TILs show in vitro cross-reactivity for allogeneic tumors but have not been evaluated for in vivo activity. METHODS: An F1 hybrid mouse (C57BL/6 X DBA-2[B6D2 F1]) was used to generate TILs (F1 TILs) expressing both H-2b and H-2d class I major histocompatibility complex (MHC) determinants, which were used to treat established autologous lung metastases in C57BL/6 (B6) parental strain mice. RESULTS: H-2b mice bearing the fully syngeneic MC-38 tumor were treated with F1 TILS, and a 98-100% reduction in 4-day-old established lung metastasis was achieved. However, B6 mice bearing MC-38 tumors after preimmunization with H-2d splenocytes did not show a response to F1 TILs. Preimmunization of B6 mice by intravenous injection of H-2d splenocytes at varying times before F1 TIL administration showed a dramatic reduction in F1 TIL efficacy when alloimmunization occurred as early as 2 days before therapy. Immunization against an unrelated haplotype (H-2s) sharing no MHC genes with the F1 TILs resulted in a smaller reduction of F1 TIL efficacy, possibly due to shared minor determinants. CONCLUSION: Allogeneic TILs sharing an MHC restriction element for a common tumor antigen can be used to successfully treat established metastases in the nonallosensitized host.

Adenocarcinoma↗
PubMed1999

Th1 cells that adoptively transfer experimental hypersensitivity pneumonitis are activated memory cells.

Cultured murine CD4+ T cell lines from Saccharopolyspora rectivirgula-sensitized donors with cytokine secretion characteristics of Th1 cells can adoptively transfer murine experimental hypersensitivity pneumonitis (EHP), whereas Th2 CD4+ cell lines cannot (Cell Immunol 177:169-175, 1997). To assess the differences between these cell lines that may be related to the ability to transfer EHP, we determined cell surface markers that distinguish naive from activated/memory cells that indicate activation and that mediate endothelial adhesion. Both Th1 and Th2 T cell lines are CD4+, CD11a+, ICAM-1+, and L-selectin negative. Th1 cells are CD49d (alpha 4) and LPAM (alpha 4 beta 7) positive, with 32% and 42% of the apparent membrane site density quantitated as the mean molecules of equivalent soluble fluorochromes (MESF) values of unstimulated spleen cells, respectively. Th2 cells are weakly alpha 4 and alpha 4 beta 7 positive, with 15% and 11% of the MESF of unstimulated spleen cells. Th1 cell lines are CD45Rb negative and CD44+, whereas Th2 cell lines are CD45Rb intermediate and CD44-/low. Th1 cells are CD25 (IL-2 receptor) low and Th2 cells CD25 high. We conclude that Th1 cells capable of transfer are activated/memory T cells, and Th2 cells incapable of transfer lack some characteristics of memory/activated T cells (i.e., increase of CD44 and decrease of CD45Rb). Both Th1 and Th2 cell lines express alpha 4 beta 7 and alpha 4 (Th1 > Th2), suggesting that alpha(4) integrin may be important in conferring ability to cells to adoptively transfer EHP.

Adoptive Transfer↗
PubMed2002

Adoptive cancer immunotherapy: discovering the best targets.

Numerous animal and clinical studies have shown that injection of T lymphocytes from a major histocompatibility complex matched donor can cure subjects with chemotherapy-resistant hematological malignancies. This graft-versus-tumor effect, which represents the most conclusive evidence that the immune system can cure cancer in humans, is mediated primarily if not exclusively by T cells specific for host minor histocompatibility antigens. Since minor histocompatibility antigens are present on all tissues and organs, injection of unselected donor T cells also causes graft vs. host disease, which drastically limits the use and benefits of this treatment. Recent studies in mice have shown that adoptive transfer of primed T cells targeted to a single major histocompatibility complex class I restricted immunodominant minor histocompatibility antigen can eradicate leukemia cells without causing any toxicity to the host. We present the promises and caveats of this and other new approaches for adoptive T cell immunotherapy of cancer.

Adoptive Transfer↗
PubMed2005

Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.

We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique "compact" morphology compared to the "loose" morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1(+) vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1(+) vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.

Adoptive Transfer↗
PubMed2005

Adoptive T cell therapy of solid cancers.

The development of immune-based approaches for the treatment of cancer has been actively investigated for many years. One strategy that has emerged as a potentially effective strategy for the treatment of aggressive established malignancies is adoptive T cell therapy. The power of this approach has been repeatedly observed in preclinical animal models. However, moving from homogeneous animal models to the heterogeneous human clinical setting has been very difficult. It is only in recent times that we have been able to pinpoint the problems of the clinical translation of adoptive T cell therapy. Some of the major problems are sources of tumor-specific T cells, ex vivo expansion, persistence, and anti-tumor activity. This review overviews the nature of these problems and some of the emerging solutions.

Animals↗
PubMed2000

Local injections of OK432 can help the infiltration of adoptively transferred CD8+ T cells into the tumor sites and synergistically induce the local production of Th1-type cytokines and CXC3 chemokines.

The effect of local injections with streptococcal preparation OK432 on the antitumor effect induced by adoptive immunotherapy (AIT) was investigated. Draining lymph node cells on day 14 after B7-P815 inoculation were used for AIT after in vitro stimulation. AIT on days 7 and 10 showed no effect on the growth of s.c. established P815 mastocytoma, but local injections with OK432 into the tumor sites on days 3, 6 and 9 resulted in a moderate antitumor effect. On the other hand, the combination therapy significantly suppressed tumor growth, and the tumor-bearing mice survived longer than those receiving only one of the treatment modalities. The significant infiltration of CD4+ or CD8+ T cells and multiple necrosis in the tumor sites were observed only when the tumor-bearing mice were treated with the combination therapy. In addition, a transfer experiment using labeled effector cells revealed these infiltrated CD8+ T cells and CD4 T cells to be derived from the donor and the host respectively. More importantly, the combination therapy clearly led to higher expression of the mRNA for Th1-type cytokines and CXC3 chemokines in the tumor sites than resulted from each of the treatment modalities alone. Collectively, these results indicate that local injections with OK432 can help the infiltration of adoptively transferred CD8+ T cells into the tumor sites and synergistically induce the local production of the Th1-type cytokines and CXC3 chemokines.

Animals↗
PubMed1997

Adoptive transfer of cytotoxic T lymphocytes induced by CD86-transfected tumor cells suppresses multi-organ metastases of C1300 neuroblastoma in mice.

In this study, we examined the therapeutic antitumor effect of cytotoxic T lymphocytes (CTL) generated against CD86-transfected mouse neuroblastoma C1300. We first generated the transfectant, CD86 + C1300, expressing a high level of mouse CD86 on the cell surface. While CD86 + C1300 cells were rejected in syngeneic A/J mice when inoculated subcutaneously, neither vaccination nor any therapeutic antitumor effect was obtained, implying that C1300 may be a poorly immunogenic tumor. However, in vitro stimulation of splenocytes from either C1300-bearing or CD86 + C1300-rejecting mice with CD86 + C1300 cells resulted in remarkable CTL activity against C1300 cells. The CTL activity induced by CD86 + C1300 was mediated by T cell receptor/CD3 and CD8 and was further enhanced by the addition of interleukin-2. Intravenous inoculation of C1300 cells led to multiple organ metastases including the liver, lung, kidney, ovary, lymph node and bone marrow. To examine the therapeutic effect of CTL in this metastasis model, CTL induced by parental or CD86 + C1300 cells were administrated into C1300-bearing mice. Adoptive transfer of CD86 + C1300-induced CTL resulted in marked elimination of multi-organ metastases and prolonged survival in almost all mice, 70% of which survived indefinitely. These results indicate that adoptive transfer of CTL induced by CD86-transfected tumor cells in vitro would be effective and useful for tumor immunotherapy against poorly immunogenic tumors.

Animals↗
PubMed2002

Adoptive transfer-experimental allergic neuritis in newborn Lewis rats results in inflammatory infiltrates, mast cell activation, and increased Ia expression with only minor nerve fiber degeneration.

Experimental allergic neuritis (EAN) induced in the Lewis rat by the adoptive transfer of a P2-specific T cell line (AT-EAN) is considered an animal model of Guillain-Barré syndrome. It is not yet known whether AT-EAN is inducible at early stages in the development of the peripheral nervous system (PNS) or whether disease activity is modified because of immaturity of either the nervous system or the immune system. We therefore compared the susceptibility of neo-natal and adult Lewis rats to AT-EAN induced by the adoptive transfer (intraperitoneally) of 10(6) activated P2-specific T cells. P2 antigen was already present in 7 day old Lewis rats and P2-specific T cell transfer into 3-day-old rats induced clinical disease associated with an inflammatory response (sciatic nerves and spinal ganglia). In injected newborn rats we observed local activation of mast cells, infiltration of the PNS by inflammatory cells, and induction of Ia antigen expression in Schwann cells. Unlike in adults, segmental or paranodal demyelination despite occasional nerve fiber degeneration did not occur. However, the difference between newborn and adult rats could not be ascertained statistically because of the relative rarity of the lesions, their focal character, the admixture of fiber demyelination and degeneration, and most importantly, size differences of the myelinated fibers, which result in a large developmental decrease in fiber density in adults compared to newborns.

Adoptive Transfer↗
PubMed2002

Family, twin, and adoption studies of bipolar disease.

Bipolar disease features states of severe depression that usually fluctuate with at least one episode of intense elation or mania. It is a disorder that has been thought for some time to have a heritable component. The lifetime prevalence of bipolar disease in the general population is approximately 1%. In contrast, family studies have shown the approximate lifetime risk of a first-degree relative of a bipolar proband to be 5% to 10%. Moreover, studies of monozygotic twins show that their risk of contracting the disease is as much as 75 times greater than that for the general population. In addition, adoption studies have demonstrated that biological relatives of bipolar patients are substantially more likely to have the disorder than are adoptive relatives.

Adoption↗
PubMed1990

Adoptive transfer of experimental allergic encephalomyelitis: conditions influencing memory and effector cell development.

The cellular transfer of clinical experimental allergic encephalomyelitis (EAE) with immune spleen cells is only accomplished following lymphoid cell stimulation during an intervening in vitro culture activation period. Recipients of these cells recover from the ensuing adoptively transferred paralytic episode and subsequently respond to active challenge with myelin basic protein (BP)-CFA in an accelerated time frame consistent with the presence of memory cells in the initial cell transfer inoculum. We have found that the addition of anti-CD4 antibody or dexamethasone during the activation period inhibits the development of the transfer active EAE effector cell subpopulation, but does not alter the in vitro development and subsequent expression of the BP-specific memory cell subpopulation. Additional experiments also suggest the development of memory cells in the absence of effector cell activity. PMA + ionomycin when used as a stimulus during the culture activation period leads to effector and memory cell development. The stimulation response is dose dependent, in that a reduced concentration of PMA + ionomycin does not lead to EAE effector cell development; however, at these reduced levels of PMA + ionomycin, memory cell development still occurred. Additional evidence which supports the concept of independent development of memory cells and effector cells was obtained with a BP-specific cell line. Following recovery from cell line-mediated clinical EAE, as well as following adoptive transfer of the cell lines in the precursor stage, cell recipients did not develop an early onset of active EAE when subsequently immunized with BP-CFA. Thus the BP-specific T-cell line appears to contain the precursors of the effector cell subpopulation but does not appear to contain the BP memory cell subpopulation. Collectively these observations suggest the existence of distinct T-cell subsets or pathways of development that are followed during the response to BP as measured by the development of clinical EAE.

Animals↗
PubMed1991

Hymenolepis nana: adoptive transfer of protective immunity and delayed type hypersensitivity response with mesenteric lymph node cells in mice.

A marked degree of footpad swelling was observed in BALB/c mice infected with Hymenolepis nana eggs, when soluble egg antigen was injected into their footpads 4 to 21 days after the egg infection, indicating delayed type hypersensitivity responses in infected mice. Adoptive transfer with mesenteric lymph node cells from donor mice (BALB/c strain; +/+) infected with eggs 4 days before cell collection could confer this hypersensitivity to recipient nude mice (BALB/c strain; nu/nu). These mesenteric lymph node cells were then divided into two fractions, blast-enriched and blast-depleted cells, by density gradient centrifugation with Percoll. The recipients intravenously injected with the blast-depleted cell fraction showed a marked increase in footpad thickness, whereas the intravenous transfer of the blast-enriched cell fraction resulted in an insignificant increase in footpad thickness. The transfer of the blast-enriched cell fraction, but not of the blast-depleted cell fraction, conferred a strong adoptive immunity on syngeneic recipient nude mice, when the immunity transferred was assessed by examining cysticercoids developed in the intestinal villi on Day 4 of challenge infection. The lack of delayed type hypersensitivity response in mice that received the blast-enriched cell population was not due to a lack of the capacity of the cells to induce the response, because the cells were capable of inducing a significant increase in thickness of footpads of normal mice when these cells were locally injected into the footpad together with soluble egg antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Large-scale expansion in interleukin-2 of tumor-infiltrating lymphocytes from patients with ovarian carcinoma for adoptive immunotherapy.

Tumor infiltrating lymphocytes (TIL) from malignant ascites or solid tumor specimens obtained from patients with ovarian carcinoma were expanded to large numbers in vitro (10(10)-10(11)) by a four-step method using AIM V medium and low concentrations of recombinant interleukin-2 (rIL-2). The expansion procedure employed 24-well culture plates, T-flasks, polyolefin gas-permeable bags (PGPB), and an artificial capillary culture system (ACCS). The mean number of mononuclear leukocytes introduced into the 24-well plates was 16.5 +/- 4.2 x 10(6) cells. TIL from a total of 16 patients were expanded only through the first three steps of the process (24-well-plates, T-flasks, and PGPB) with an overall expansion of 255 +/- 99 fold and mean duration of 27.4 +/- 2.2 days. TIL from 9 of 16 patients were expanded further through the fourth step (ACCS) of the expansion method. The cumulative fold-expansion in nine patients was 8044 +/- 4807 (mean +/- SEM), the median was 2876 and the mean expansion time was 47.1 +/- 4.7 days. TIL from seven additional patients did not grow in rIL-2. Six of these 7 patients received chemotherapy at least four weeks before the specimens were collected. Two ACCS were used in parallel to facilitate expansion of TIL. Viable rIL-2-expanded TIL in the range of 1 x 10(10)-1 x 10(11) were recovered from the two ACCS, a number sufficient for adoptive immunotherapy of patients with ovarian carcinoma. The rIL-2-expanded TIL were predominantly CD3+ CD4+ CD8- alpha beta TCR+, although CD3+ CD4- CD8+ alpha beta TCR+ T cell lines were obtained from certain patients. An increase (43 +/- 8 vs 75 +/- 13; P = 0.05) in the proportion of CD4+ cells was observed over the duration of the four expansion steps. However, CD8+ TIL-derived T cells lines were also expanded in the ACCS. The four-step expansion method described here has several significant advantages over existing techniques. It requires substantially less personnel, equipment and space and the risk of contamination during expansion of the cultures is decreased. These results demonstrate that the four-step method described here can be effectively used for the large-scale expansion of ovarian TIL for the treatment of patients with ovarian carcinoma by adoptive immunotherapy.

Antigens, CD↗
PubMed1991

Adoptive transfer of experimental allergic encephalomyelitis and localization of the encephalitogenic epitope in the SWR mouse.

Adoptively-transferred experimental allergic encephalomyelitis (EAE) was induced in the SWR (H-2q) strain of mouse using lymph node cells, spleen cells, or cell lines sensitized to whole myelin basic protein (MBP). With the aid of synthetic peptides, the minimal encephalitogenic epitope of MBP for the SWR strain was localized to amino acids 87-99 of the MBP molecule. The 87-99 sequence is also encephalitogenic for the SJL strain of mouse and the Lewis rat. EAE was induced with a protocol similar to that for the induction of EAE in the SJL strain with the exception that sublethal irradiation of recipients was necessary. Mice developed typical clinical and pathological EAE 6-14 days post-transfer of cells sensitized to either whole MBP or peptide 87-99, after which they remitted. No relapses were observed. Thus, adoptively transferred EAE can be induced in irradiated H-2q mice for which the encephalitogenic epitope is one of the nested encephalitogenic epitopes for SJL (H-2s) mice, namely residues 87-99.

Animals↗
PubMed1995

Oral administration of human or murine interferon alpha suppresses relapses and modifies adoptive transfer in experimental autoimmune encephalomyelitis.

Chronic relapsing experimental autoimmune encephalitis (CR-EAE) is an inflammatory process of the central nervous system (CNS) that closely resembles the human disease multiple sclerosis (MS). EAE was induced in SJL/J mice and following recovery from the initial attack, animals were fed varying doses of human or murine interferon alpha (IFN-alpha), or mock IFN three times per week. After relapse, concanavalin A-activated spleen cells were transferred adoptively from orally fed animals into recipient animals. Oral administration of human or murine IFN-alpha suppressed relapse in actively immunized animals, modified adoptive transfer of EAE, and decreased mitogen/antigen proliferation and IFN-gamma secretion in both donors and recipients. IFN-alpha acts orally by modifying the encephalitogenicity of donor spleen T cells.

Administration, Oral↗
PubMed1994

Autolymphocyte therapy--I. In vivo tumour-specific adoptive cellular therapy of murine melanoma and carcinoma using ex vivo activated memory T-lymphocytes.

Autolymphocyte therapy (ALT) is tumour-specific adoptive cellular therapy of neoplastic disease based upon non-specific ex vivo activation of autologous peripheral blood lymphocytes (PBL), using the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC). To determine the requirement for tumour antigen during the activation process, splenocytes from C57BL/6J healthy syngeneic mice (HSM) and tumour-bearing mice (TBM) were activated ex vivo using a MLC-supernatant (MLCS). Ex vivo activation was performed both in the presence (HSM splenocytes) and absence (TBM splenocytes) of a 3M KC1 syngeneic tumour-antigen (STA) extract prepared from Lewis lung (3LL) carcinoma, B16 melanoma, or normal lung. Immunophenotyping of splenocytes pre- and post-activation by MLCS plus STA or MLCS only revealed expansion of activated CD44+ (memory) T-cells. Ex vivo tumour-specific cytotoxicity was demonstrated using MLCS-activated (TBM) or MLCS + STA-activated (HSM) splenocytes against 3LL or B16 target cells. CD44+ T-cells (ALT-cells) were then infused into synegeneic 3LL and B16 TBM. Significant antitumour activity was detected in 3LL and B16 TBM receiving cells from normal mice that were activated with MLCS in the presence of 3LL or B16 STA, respectively, and in 3LL and B16 TBM receiving splenocytes from 3LL-TBM and B16-TBM, respectively, activated by MLCS alone. Infusions of 3LL-derived or B16-derived ALT-cells into HSM provided specific immunity on tumour challenge. No antitumour activity was seen in 3LL and B16 TBM receiving fresh TBM splenocytes, ALT-cells derived from HSM which were activated ex vivo using MLCS without antigen, normal lung tissue as antigen, or using MLCS-activated splenocytes without STA derived from reciprocal TBM. Ex vivo depletion of CD44+ cells or Thy-1.2+ T-cells abrogated all antitumour activity in TBM and in HSM challenged with tumour. Depletion of NK-1.1+ natural killer (NK)-cells had no effect on antitumour efficacy. These data suggest that tumour-specific adoptive cellular therapy is possible using ex vivo activated HSM splenocytes with STA, or TBM splenocytes activated ex vivo without STA, and that these antitumour effects are dependent on CD44+ memory T-cells.

Animals↗