Targeting Human γδ T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer

Abstract

The increasing evidence that ;D T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormonerefractory prostate cancer to examine the feasibility and consequences of using the ;D T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood ;D cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant longterm shift of peripheral ;D cells toward an activated effectormemory-like state (T EM ), producing IFN-; and perforin. These patients also maintained serum levels of tumor necrosis factorrelated apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by ;D cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T EM ;D cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either ;D cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, ;D cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. [Cancer Res 2007;67(15):7450-7]

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…Naturally, local access to inflamed tissues and draining lymph nodes in humans is very limited, thereby severely compromising investigations into the APC function of Vc9/Vd2 T cells -or, as a matter of fact, into the APC function of any human immune cell. Indirect support for a possible role as APC stems from observations that HLA-DR is expressed by activated Vc9/Vd2 T cells in patients with severe inflammation or during acute infection [123,[138][139][140], and in patients receiving intravenous zoledronate with and without IL-2 [65,141,142]. However, functional evidence into the potential of activated Vc9/Vd2 T cells to act as APC ex vivo is only beginning to emerge [123,143].…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…36 Subjects were randomized into two groups, which received either zoledronate alone (group A: 4 mg i.v. every 21 days) or zoledronate with IL-2 (group B: identical dose of zoledronate, plus 0.6 million IU IL-2 s.c. immediately after zoledronate).…”

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity

“…cdT cells can directly recognize antigens without MHC restriction, 12 have a wide antigen recognition spectrum, which includes protein antigens and phosphoantigens 13 and can directly kill several tumor types including colorectal, lung, prostate, ovarian and renal cell carcinomas. 16,18,25,28,29 Because of these features, cdT cells are an interesting candidate effector for antitumor immune therapy. There are two commonly available strategies for using cdT cells in cancer therapy.…”

“…c9d2T cells belong to the major subset of cdT cells in peripheral blood, and are regarded as a potential candidate for tumor immunotherapy because this subset has been shown to display strong antitumor activity against different type of cancer cells. [16][17][18][19][20] However, the low frequency of c9d2T cells in peripheral blood greatly limits their potential clinical applications. c9d2T cells account for only 2-5% of the total peripheral blood T-cell repertoire.…”