Novel Therapies for Renal Cell Cancer

Mayer N. Fishman

The discovery of diverse details of the genetics, cell biology, and pathology of disease and the extensive infrastructure for synthesis and testing of targeted drugs or immune strategies are a basis to be hopeful that innovative, effective, widely applicable therapies can be realized for metastatic kidney cancer. High-dose inter-leukin-2 has been the sole medical therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic renal cancer, and interferon-a, also in widespread use, has had approval in Europe. Over 100 published single-arm/single-drug kidney cancer trials, many based on sound preclinical hypotheses, would seem to be a basis for pessimism. Partial response and disease stabilization at high frequency are now reported among the "targeted-drug" approaches in current testing. Whereas progress in conventional cytotoxics has largely bypassed renal cancer, and immune therapies have had dramatic success limited to a minority of patients, some therapies may turn out to be broadly tolerated and efficacious. This is an era for optimism for the application of new technology to kidney cancer therapy.

Looking backward, little seems more precarious than the optimistic projections for clinical trial strategies based on the experience of ex vivo preclinical tests, in vitro testing of cell lines, or murine models. Favorable results of uncontrolled series must be confirmed with randomized testing. The interval from initial safety testing until availability for clinical use routinely exceeds 5 years. Good news of early responders in phase I trials travels fast, along with frustration about the absence of access to drugs in early development. Nonetheless, these preclinical and early-phase trials are a key part of the means by which new compounds or strategies arrive for testing in pivotal clinical trial testing. Much attention is focused on looking for early respon-ders in early phase and proof-of-principle trials. This is particularly true for renal cancer. This chapter presents a snapshot of the variety of approaches in this pipeline between successful model systems to matured disease-specific phase III trial. The acceptance of new therapy must be anticipated to be contingent on phase III trial testing; to this point, tempered enthusiasm for single-arm trials' results remains appropriate.

The renal cancer population is relatively heterogeneous whether evaluated by conventional histology, prognostic models, site of metastasis, or novel markers. This leads to difficulty in selecting promising approaches based on isolated responders in early-phase trials. Through most of the period of testing, many of the compounds are available for clinical use only in investigational trials. Often the trials have entrance criteria that appear restricted to a fraction of the available, interested population. A common pattern in 2005 is zero or one previous immunotherapy treatment, and clear cell subtype only, and no central nervous system (CNS) metastasis history. For the individual patient seeking a particular compound, a working knowledge of trial databases such as cancer.gov, www.nkca.org, and regional cancer

Fig. 18.1. Diagram illustrating the diverse concepts in preclinical and translational application to the problem of therapy for kidney cancer.

Novel Therapies for Renal Cell Cancer

Conventional targets: • DNA

•Microtubules

"Targeted"drugs:

•Cytoplasm & surface Nonspecific mmimit-yr receptor tyrosine kinases •IL-2, IFN

•Other enzymatic processes •Retinoids, other cytokines

"Targeted"drugs:

•Cytoplasm & surface Nonspecific mmimit-yr receptor tyrosine kinases •IL-2, IFN

•Other enzymatic processes •Retinoids, other cytokines

Immune cell maneuvers •T-cells

•Dendritic cells •Stem cells

Tumor-derived products: '•Tumor lysate Isolated proteins (HSP-P96) Modified tumor cells

Immune cell maneuvers •T-cells

•Dendritic cells •Stem cells centers may be especially useful. A Web site that incorporates critiques of ongoing trials as well as patient-directed conceptual discussions is cancerguide.org.

Many approaches are in contemporary development (Fig. 18.1). The major categories considered here include drugs that attack conventional targets, that is, DNA or microtubules; "targeted drugs" that affect enzymatic function of other surface, nuclear, or cytoplasmic proteins; drugs influencing general immunity; immune products derived from tumor material; immune maneuvers using leukocytes including T cells, dendritic cells, or stem cells; and finally, treatments attacking the unique physiology of tumor-associated blood vessels. Some therapeutic strategies encompass multiple categories, as do some combination approaches. Any novel approach is potentially of scientific or clinical interest; it is often unclear what "drug class" should be assigned to particular product. New testing approaches and understanding patterns of failure can lead indirectly to improvements of clinical utility.

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