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Background: Adoptive cell transfer of tumor infiltrating lymphocytes has shown clinical efficacy in the treatment of melanoma and is now also being explored in other tumor types. Generation of sufficient numbers of effector T cells requires extensive ex vivo expansion, often at the cost of T cell differentiation and potency. For the past 20 years, IL-2 has been the key cytokine applied in the expansion of TIL for ACT. However, the use of IL-2 has also led to collateral expansion of regulatory T cells (Tregs) and progressive T cell differentiation, factors known to limit in vivo persistence and activity of transferred TIL. The use of alternative T cell growth factors is therefore warranted. Here, we have compared the effects of IL-2, -15 and -21 cytokines on the expansion and activation of TIL from single-cell suspensions of non-small cell lung cancer, ovarian cancer and melanoma. Methods: We applied the K562-based artificial APC (aAPC) platform for the direct and rapid expansion of tumor infiltrating lymphocytes isolated from primary cancer specimens. These aAPC were engineered to express the Fc-γ receptor CD32 (for anti-CD3 antibody binding), the co-stimulatory molecule 4-1BBL, and to secrete either IL-2, IL-15 or IL-21 cytokine. Results: Although IL-2 aAPC induced the greatest overall TIL expansion, IL-21 aAPC induced superior expansion of CD8+ T cells with a CD27+CD28+ "young" phenotype and superior functional cytotoxic effector characteristics, without collateral expansion of Tregs. Conclusion: Our data rationalize the clinical application of IL-21-secreting aAPC as a standardized cell-based platform in the expansion of "young" effector TIL for ACT. [ABSTRACT FROM AUTHOR]

Previous vaccination studies in patients with castration-resistant prostate cancer (CRPC) showed improved survival without prolongation of progression-free survival (PFS). This might be explained by enhanced efficacy of subsequent therapies because of heightened immune status. We therefore evaluated the efficacy of chemotherapy in CRPC patients after immunotherapy. We retrospectively analyzed 28 patients who were treated with ipilimumab and GVAX, an allogeneic vaccine, and 21 patients who were randomized to GVAX or no vaccination. To study whether immune status was related to the efficacy of chemotherapy, frequencies of myeloid and lymphocyte subsets were determined. Of 28 patients treated with GVAX and ipilimumab, 23 patients received docetaxel and 13 patients mitoxantrone. Median PFS after docetaxel was 6.4 mo (range 0.8–11.2), while median PFS after mitoxantrone was markedly longer than expected (4.8 mo; range 1.4–13.7). High CD8+ICOS+Tcell/Treg and pDC/mMDSC ratios were associated with relatively long PFS after mitoxantrone, suggesting a correlation between activated immune status and benefit of mitoxantrone. Analysis of 21 patients, randomized to GVAX or not, revealed a median PFS after docetaxel of 9.9 mo for vaccinated patients and 7.1 mo for unvaccinated patients. Interestingly, PFS after mitoxantrone (n = 14) was significantly longer in vaccinated patients as compared to controls (5.9 vs. 1.6 mo,p = 0.0048). In conclusion, mitoxantrone seems more effective in CRPC patients after immunotherapy, which may be related to the immune-stimulating effect of mitoxantrone in patients with heightened antitumor immunity. As this was a retrospective study with limited sample size, prospective studies are warranted to definitively show proof of principle. [ABSTRACT FROM AUTHOR]

Background: Adoptive cell transfer of tumor infiltrating lymphocytes has shown clinical efficacy in the treatment of melanoma and is now also being explored in other tumor types. Generation of sufficient numbers of effector T cells requires extensive ex vivo expansion, often at the cost of T cell differentiation and potency. For the past 20 years, IL-2 has been the key cytokine applied in the expansion of TIL for ACT. However, the use of IL-2 has also led to collateral expansion of regulatory T cells (Tregs) and progressive T cell differentiation, factors known to limit in vivo persistence and activity of transferred TIL. The use of alternative T cell growth factors is therefore warranted. Here, we have compared the effects of IL-2, -15 and -21 cytokines on the expansion and activation of TIL from single-cell suspensions of non-small cell lung cancer, ovarian cancer and melanoma.Methods: We applied the K562-based artificial APC (aAPC) platform for the direct and rapid expansion of tumor infiltrating lymphocytes isolated from primary cancer specimens. These aAPC were engineered to express the Fc-γ receptor CD32 (for anti-CD3 antibody binding), the co-stimulatory molecule 4-1BBL, and to secrete either IL-2, IL-15 or IL-21 cytokine.Results: Although IL-2 aAPC induced the greatest overall TIL expansion, IL-21 aAPC induced superior expansion of CD8+ T cells with a CD27+ CD28+ "young" phenotype and superior functional cytotoxic effector characteristics, without collateral expansion of Tregs.Conclusion: Our data rationalize the clinical application of IL-21-secreting aAPC as a standardized cell-based platform in the expansion of "young" effector TIL for ACT. [ABSTRACT FROM AUTHOR]