Microenvironment to Immunotherapy Clinical Trials

There are two principal implications of the results uncovered by studies of the metastatic melanoma tumor microenvironment. First, it is plausible to perform pretreatment tumor biopsies to examine features of the tumor microenvironment that may correlate with clinical response to melanoma vaccines. Identifying a molecular signature linked to clinical outcome should ultimately be able to guide patient selection for such studies. We have performed such a prospective analysis

Tumor cell

Cytotoxic granules

Tumor cell

Apoptotic tumor cell

(f^ I Survivin

CTL MpO- f Serpins

(f^ I Survivin

CTL MpO- f Serpins

Surviving tumor cell

Fig. 4.3 Tumor cell-intrinsic resistance to T cell-mediated apoptosis. CTL-mediated lysis of tumor cells can be vigorous in the absence of potent anti-apoptotic pathways (upper panel). It is speculated that upregulated expression of survivin, serpins, and Notch signaling may generate melanoma cells that are relatively resistant to apoptosis triggered by CTL granule exocytosis (lower panel).

with 19 metastatic melanoma patients participating in a multipeptide melanoma vaccine trial. A small subset of transcriptional differences in the tumor biopsies was found to distinguish clinical responders from non-responders. Interestingly, among these was a set of chemokine genes more highly expressed in the responding patients (Gajewski et al., unpublished data). While this is a small sample size that will require confirmation, it is beginning to connect the biology of melanoma and the antitumor immune response with clinically relevant information.

The second implication of such gene expression profiling is to identify the relevant barriers that can be overcome with new immunotherapeutic interventions. Ultimately, one can envision an individualized patient therapy in which a tumor is biopsied to determine major potential barriers to effective antitumor immunity (e.g. absence of chemokines, over overexpression of specific negative regulatory mechanisms) then instituting the appropriate therapy to overcome those barriers in concert with active immunization or adoptive T cell transfer. Some such combination strategies are already being explored clinically, albeit with less selected patients. Vieweg and colleagues were the first to report on the use of Ontak (an IL-2-diptheria toxin fusion protein) to decrease the numbers of CD4+ CD25+ FoxP3+ Tregs in patients in combination with a dendritic cell-based vaccine [49].

The TIL adoptive transfer approach of Rosenberg and colleagues has been found to be most effective when combined with a chemotherapy conditioning regimen that supports homeostatic proliferation of the transferred cells [19], which preclinical data argues helps to maintain T cell function and prevent anergy induction [29]. Howard Kaufman has explored intratumoral injection of a vaccine virus vector encoding human B7-1 in patients with advanced melanoma, and observed clinical activity in a subset of patients [50]. A neutralizing anti-PD-1 mAb developed by Medarex is entering phase I clinical trials soon, and clinical-grade 1-methyltryp-tophan also is being manufactured. Thus, it is conceivable that antagonizing PD-L1/ PD-1 interactions and IDO activity in combination with vaccines or adoptive T cell transfer also may be possible in the near future. Individualizing such therapies should ultimately be possible by performing molecular analyses on pretreatment tumor biopsies to identify the most relevant tumor resistance mechanisms in individual cases.

Acknowledgments The laboratory contributions of Helena Harlin, Yuru Meng, Mark McKee, Craig Slingluff, Ian Brown, and Justin Kline are enormously appreciated. I also acknowledge the technical contributions of Alpana Sahu and Todd Kuna. This work relied heavily upon the University of Chicago Functional Genomics and Human Immunologic Monitoring core facilities, and was supported by NIH grants R01 CA90575 and P01 CA97296, a Translational Research Award from the Burroughs Wellcome Fund, and as a grant from the Ludwig Trust.

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