In Vitroactivated Lak And Til Cells

Animal studies have shown that lymphocytes can be activated against tumor antigens in vitro by culturing them with x-irradiated tumor cells in the presence of IL-2 and added tumor antigens. These activated lymphocytes mediate more effective tumor destruction than untreated lymphocytes when they are reinjected into the original tumor-bearing animal. It is difficult, however, to activate in vitro enough lymphocytes with antitumor specificity to be useful in cancer therapy.

While sensitizing lymphocytes to tumor antigens by this method, S. Rosenberg discovered that, in the presence of high

Melanocytes Photomicrograph

Photomicrographs of cultured normal melanocytes (top) and cultured cancerous melanoma cells (bottom) in the presence (left) and absence (right) of tumor necrosis factor (TNF-a). Note that, in the presence of TNF-a, the cancer cells stop proliferating, whereas TNF-a has no inhibitory effect on proliferation of the normal cells. [From L. J. Old, 1988, Sci. Am. 258(5):59.]

FIGURE 22-12

Photomicrographs of cultured normal melanocytes (top) and cultured cancerous melanoma cells (bottom) in the presence (left) and absence (right) of tumor necrosis factor (TNF-a). Note that, in the presence of TNF-a, the cancer cells stop proliferating, whereas TNF-a has no inhibitory effect on proliferation of the normal cells. [From L. J. Old, 1988, Sci. Am. 258(5):59.]

concentrations of cloned IL-2 but without the addition of tumor antigens, large numbers of activated lymphoid cells were generated that could kill fresh tumor cells but not normal cells. He called these cells lymphokine-activated killer (LAK) cells. In one study, for example, Rosenberg found that infusion of LAK cells plus recombinant IL-2 into tumor-bearing animals mediated effective tumor-cell destruction (Figure 22-13). LAK-cell populations are typically >90% activated NK cells. However, small numbers of TCR-bearing cells are present in LAK populations and it is possible that these may also contribute to their tumoricidal activity.

Because large numbers of LAK cells can be generated in vitro and because these cells are active against a wide variety of tumors, their effectiveness in human tumor immunother-apy has been evaluated in several clinical trials. In these trials, peripheral-blood lymphocytes were removed from patients with various advanced metastatic cancers and were activated in vitro to generate LAK cells. In an early study, patients were then infused with their autologous LAK cells together with IL-2. In this trial, which involved 25 patients, cancer regression was seen in some patients. Subsequently, a more extensive trial with 222 patients resulted in complete regression in

16 patients. However, a number of undesirable side effects are associated with the high levels of IL-2 required for LAK-cell activity. The most noteworthy is vascular leak syndrome, in which lymphoid cells and plasma emigrate from the peripheral blood into the tissues, leading to shock.

Tumors contain lymphocytes that have infiltrated the tumor and presumably are taking part in an antitumor response. By taking small biopsy samples of tumors, one can obtain a population of these lymphocytes and expand it in vitro with IL-2. These activated tumor-infiltrating lymphocytes are called TILs. Many TILs have a wide range of antitumor activity and appear to be indistinguishable from LAK cells. However, some TILs cells have specific cytolytic activity against their autologous tumor. These tumor-specific TILs are of interest because they have increased antitumor activity and require 100-fold lower levels of IL-2 for their activity than LAK cells do. In one study, TIL populations were expanded in vitro from biopsy samples taken from patients with malignant melanoma, renal-cell carcinoma, and small-cell lung cancer. The expanded populations of TILs were reinjected into autologous patients together with continuous infusions of recombinant IL-2. Renal-cell carcinomas and malignant

Without IL-2

With IL-2

None

Cultured spleen cells

Fresh spleen cells

LAK cells

Cells transferred

FIGURE 22-13

Experimental demonstration of tumor-destroying activity of LAK cells plus IL-2. Spleen cells or LAK cells, in the presence or absence of recombinant IL-2, were infused into mice with pulmonary sarcoma. The animals were evaluated 13 days later for the number of pulmonary sarcoma metastases. The LAK cells were prepared by isolating lymphocytes from tumor-bearing animals and incubating them in vitro with high concentrations of IL-2. Note that LAK cells caused tumor regression only when IL-2 was also infused. [Data from S. Rosenberg et al, 1988, Ann. Int. Med., 108:853.]

melanomas showed partial regression in 29% and 23% of the patients, respectively.

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