Tumor‐infiltrating lymphocytes can be activated in situ by using in vivo activants plus F(ab′)2 bispecific antibodies

Abstract

In vitro-activated T lymphocytes can be retargeted with anti-CD3 X anti-tumor bispecific antibodies (BsAb) t o kill tumor cells in vitro and in vivo. The purpose of the present study was to examine the systemic and intra-tumor effects of in vivo T-cell activation with BsAb, staphylococcal enterotoxin B (SEB), and P-glucan in combination with BsAb as a retargeting agent. CL-62 melanoma cells were injected subcutaneously into C3H/ HeN mice. Mice were subsequently treated with BsAb alone or with SEB or P-glucan plus BsAb. Fresh splenocytes, lymph-node cells and tumor-infiltrating lymphocytes (TlL) were tested for their proliferative response using incorporation of 3H-thymidine, and for their ability to lyse CL-62 cells in the presence or absence of BsAb in 4-hr S'Chromium release assays. Toxicity of treatments was assessed in a D-galactosamine model. BsAb, alone or combined with P-glucan, had essentially no effect on systemic T-cell cytotoxicity, and essentially no effect on systemic proliferation, unless exogenous IL-2 was provided. A t the tumor site, BsAb alone, BsAb plus P-glucan, and SEB plus BsAb all significantly increased BsAb-mediated TIL cytotoxicity. In contrast to the TIL-limited effects of BsAb and of BsAb plus p-glucan, SEB plus BsAb markedly increased both systemic and intra-tumor T-lymphocyte activation. Toxicity correlated with measures of systemic activation, with limited effects from BsAb alone and from P-glucan plus BsAb, and with marked lethality from SEB plus BsAb. Overall, these results suggest moderate intra-tumor activation of TIL, but no measurable systemic activation after in vivo treatment with BsAb or p-glucan plus BsAb. SEB plus BsAb results in complete T-cell activation in both systemic and intra-tumor compartments, but at the expense of increased systemic toxicity. In conclusion, TIL can be activated in situ with different combinations of in vivo activants. In vivo-activated TIL can be retargeted with bispecific antibodies to lyse tumor cells, and may be an alternative to ex vivo T-cell activation and adoptive transfer therapy.o 1996 Wiley-Liss, Inc.

Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate

“…40 days from day 80 to 120 for treated mice). Previous reports have demonstrated tumor infiltrating lymphocytes in established solid tumors after bispecific antibody treatment (Thibault et al, 1996), but few have demonstrated a reduction in solid tumor growth or prolongation of survival (Kroesen et al, 1995). The present findings are noteworthy given the difficulties posed by the bloodbrain barrier and the relative immune privilege of the brain.…”

Anthrax Toxin-Mediated Delivery In Vivo and In Vitro of a Cytotoxic T-Lymphocyte Epitope from Ovalbumin

“…The in vitro expansion of patient CTL represents a viable and promising approach for therapeutic treatment of a variety of diseases (5,9,11,17,20,22,32,33). For reasons that remain unclear, patients often mount a CTL response that recognizes cancer or infected cells but are not able to clear the defective cells.…”

Administration of BiMAb‐Retargeted T Cells in a Rat Hepatic Metastases Colon Tumour Model Results in T‐Cell Tumour Infiltration Independent of the Route of Administration

“…A‐NK cells, T cells) in combination with in vivo activants (e.g. interleukin (IL)‐2, Staphylococcal enterotoxin B) [1, 2] or BiMAb [3, 4] is an expanding modality in cancer research and therapy. For an optimal cytotoxic effect, the number of effector cells at the tumour site should be maximized.…”