Cn. Baxevanis et al., Increased generation of autologous tumor-reactive lymphocytes by anti-CD3 monoclonal antibody and prothymosin alpha, CANCER IMMU, 48(2-3), 1999, pp. 71-84
Anti-CD3 monoclonal antibody (mAb) activates in vitro peripheral blood mono
nuclear cells (PBMC) to lyse a variety of tumor cell lines in a non-major h
istocompatibility-complex(MHC)-restricted manner [subsequently referred to
as anti-CD3-activated killer (AAK) cytotoxicity]. Prothymosin alpha (ProT a
lpha) is a biological response modifier that exerts its effects primarily o
n mononuclear cells, especially when these cells' effector functions are im
paired. In this study, we report that ProT alpha enhances the AAK cytotoxic
ity in PBMC from healthy donors. This effect was more profound with cancer
patients' PBMC, which were deficient in their ability to respond with enhan
ced AAK cytotoxicity upon in vitro stimulation with anti-CD3. Thus, cancer
patients' PBMC, activated with a combination of anti-CD3 and ProT alpha, ex
hibited increased AAK activity and efficiently lysed both autologous tumor
and Daudi targets. The ProTa effect on PBMC was demonstrated to involve sti
mulation of adhesion molecules (CD2, CD18, CD54, CD49f) and CD25 expression
, up-regulation of perforin mRNA transcription, increased numbers of perfor
in-positive (+) cells and elevated production of interleukin-2 (IL-2), inte
rleukin-1 beta (IL-1 beta) and, tumor necrosis factor alpha (TNF alpha). Mo
reover, effector CD8(+) and CD56(+) cells pretreated with anti-CD3 and ProT
alpha contained high cytoplasmic perform levels and increased expression o
f IL-1 beta- and TNF alpha-specific receptors. The induction of autologous-
tumor-reactive CD8(+) and CD56(+) lymphocytes in anti-CD3-activated PBMC by
ProTa provides an alternative protocol aimed at the improvement of clinica
l results in cellular adoptive immunotherapy of cancer.