Nonspecific Immune Modulation Plus Active Immunotherapy

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Another trend emerging in the practice of active immunotherapy with personalized (and nonpersonalized) cancer vaccines is their use in combination with other nonspecific immunomodulatory agents. Again, these combination approaches are likely to be necessary in any setting more advanced than minimal residual disease (83). Moreover, if the nonspecific agents prove to be well tolerated with minimal toxicity, there may be incentive to employ them even in the setting of minimal disease burden to further decrease the likelihood of disease recurrence. The nonspecific agents include antibodies against CTLA-4 that are designed to prevent effector T cell downregulation and a large number of agents that address the problem of immune suppression in tumor-bearing hosts. With emphases on pre-clinical testing, these various agents are discussed in turn below.

Striking synergy between anti-CTLA-4 antibody and autologous GM-CSF-secreting B16 melanoma and SM1 breast tumor vaccines against established disease in mice has been observed, and the antibody has also been tested in combination with an off-the-shelf GM-CSF-secreting prostate cancer vaccine, with promising results in preclinical studies (84-86). In a preliminary study in human cancer patients previously treated with either autologous or off-the-shelf cancer vaccines who went on to receive infusion with anti-CTLA-4 antibody, only those patients who received the autologous vaccine demonstrated signals of clinical activity (87). Many additional clinical trials are underway testing anti-CTLA-4 antibody either as monotherapy or in combination with off-the-shelf peptide vaccines, GM-CSF, and off-the-shelf whole cell vaccines (88,89 and http://www.clinicaltrials.gov/). Unfortunately, there are no clinical trials currently underway testing anti-CTLA-4 antibody with personalized cancer vaccines despite the suggestion that autologous vaccines may be a particularly potent partner for this antibody. Will the dose of antibody required vary depending on what vaccine type is employed? This later question is of interest given the autoimmune-like toxicities associated with the antibody (90).

In the last 10 to 15 years, the issue of specific immune suppression in tumor-bearing hosts has moved from a concept with few tangible toe holds from which to direct therapeutic intervention to remarkable progress in identifying molecular structures and cell types that are ripe for targeting in preclinical and clinical settings. One can envision that just as different chemotherapeutics have been combined in the clinic based on unique mechanisms of action, multiple agents each working to address distinct pathways of immune suppression will be utilized in combination. A nonexhaustive list of agents, their biological targets and evidence, where available, for utility in combination with cancer vaccines are presented in Table 3. Two agents that address the problem posed by accumulation of regulatory T cells (Tregs) are discussed in some detail.

Table 3 Selected Mechanisms of Immune Suppression in Tumor-Bearing Hosts and Intervening Strategies

Form of immunosuppression

Therapeutic agent Mechanism of action

Preclinical evidence for synergy with cancer vaccines (selected examples)

Reference

Accumulation of CD4+CD25+ regulatory T cells (Tregs) expressing GITR and FoxP3 reduces effector T cell function

Accumulation of immature myeloid cells (ImCs) loss of TCR chain; block production of IFN-y by T cells

Elevated levels of indoleamine 2,3-dioxygenase (IDO) in APCs and tumor cells that degrades tryptophan effector T cell anergy/ apoptosis

Cyclophosphamide

Ontak

All-irani-retinoic acid (ATRA)

1 -methy 1-tryptophan (1MT)

Induces apoptosis in Tregs and/or downregulation of GITR and FoxP3 gene expression Binds to high-affinity IL-2 receptor expressed on Tregs; death by intracellular accumulation of toxin Induces differentiation of ImCs; restores "normal" myeloid dendritic cell/ plasmacytoid dendritic cell ratio

Competitive inhibitor of IDO, thus preventing tryptophan catabolism

See text 91-94

See text 95-100

Mice with 4-5 mm C3 101-103

or 3-5 mm Meth A fibrosarcomas treated with tumor-specific peptide in CFA or DCs transduced with p53, respectively + implanted ATRA pellet: tumor size reduced 3-5-fold vs. control

No published studies testing 104

MT1 in combination with cancer vaccines.

{Continued)

Table 3 Selected Mechanisms of Immune Suppression in Tumor-Bearing Hosts and Intervening Strategies (Continued)

Preclinical evidence for synergy

with cancer vaccines (selected

Form of immunosuppression

Therapeutic agent

Mechanism of action

examples)

Reference

B cell production of CCL4

Rituxan or other

Deplete B cells to eliminate

Tumor growth slower and

105-111

recruits CD4+CD25+ Tregs;

B cell-depleting

their deleterious effects

metastases reduced in

B cell-DC interaction —►

antibodies

on anti-tumor immunity

Met 129 breast tumor-

promotes IL-4, IL-10

bearing mice partially

production

depleted of B cells with anti-IgG/IgM sera; prolonged survival in transgenic B cell-deficient mice bearing B16 tumors vaccinated with adenovirus encoding TRP-2 compared with tumor-bearing w.t. control mice

B7-H1 expression on

Blockade with

Prevent effector T cell

83% long—term survival (80 days)

112-116

tumors —► interacts with

anti-PD-1 or

downregulation upon

in B16 tumor bearing mice

PD-1 on effector

anti-B7-Hl

infiltration into tumor

injected with autologous

T cells —► inhibits T cell

antibodies;

bed

HSP70 based vaccine in

proliferation and cytokine

complete binding

combination with gene

secretion

with soluble PD-1

encoding soluble PD-1 vs. 0% survival in controls

Cyclophosphamide has been a mainstay of cancer therapy and is typically used in combination with other chemotherapeutic drugs. In these settings, cyclophosphamide is administered at a dose that optimally causes cross-linking of DNA of rapidly dividing malignant cells. Cyclophosphamide has also been shown to have a role in immune modulation as elucidated by Robert North and others (91). It was shown that at certain doses, typically lower than those required for direct antitumor activity, cyclophosphamide selectively inhibits the activity of suppressor T cells, or what are now more commonly referred to as Tregs. This observation has been exploited in several models where the drug is given prior to administration of cancer vaccines. The premise behind this regimen is that elimination of Tregs will relieve a brake on endogenous effector T cells and/or on novel T cell specificities primed by vaccination. Berd and colleagues have combined low-dose cyclophosphamide treatment with a hapten-modified autologous melanoma vaccine strategy for many years in clinical trials (Table 2), and a pivotal study testing this approach in melanoma patients is underway (http://www.clinicaltrials.gov/). Preclinical experiments in a murine breast cancer model, also using low-dose cyclophosphamide in combination with hapten-modified autologous tumor cells, have added to the validity behind this combination approach (92). The mechanism by which cyclophosphamide inhibits the activity of Tregs in murine models is suggested to involve reduction in cell number (via apoptosis) and downregulation of GITR and FoxP3 gene expression (93,94). Given the favorable safety profile generally associated with low-dose cyclophosphamide administration and the increased understanding of its specific effect on Tregs that would allow its effectiveness to be monitored, one could envision the drug's incorporation into any number of active immunotherapy trials with the goal of reducing the deleterious effect of suppressor T cells in tumor-bearing hosts.

Ontak (denileukin diftitox) is an IL-2-diptheria toxin fusion protein that binds to the high-affinity IL-2 receptor and causes cell death. Ontak is FDA approved for treatment of cutaneous T cell lymphoma where it acts directly on malignant cells. Given that immunosuppressive T cells also express the high-affinity IL-2 receptor, recent and intensive preclinical and clinical efforts has ensued to determine whether Ontak might be useful in treatment of a number of malignancies (95-100). One of these studies tested Ontak in renal cell carcinoma patients in combination with an autologous vaccine consisting of DCs transfected with tumor-derived RNA (100). Associated with the elimination of Tregs in mice and humans treated with Ontak is enhanced levels of immunity to subsequent vaccination with various immunogens, providing a strong rationale for its ongoing investigation in immunotherapy of cancer when combined with patient-specific or off-the-shelf cancer vaccines.

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