Tumor antigen-specific T-cell tolerance limits the efficacy of therapeutic cancer vaccines. Antigen-presenting cells mediate the induction of T-cell tolerance to self-antigens. We therefore assessed the fate of tumor-specific CD4+ T cells in tumor-bearing recipients after in vivo activation of antigen-presenting cells with antibodies against CD40. Such treatment not only preserved the responsiveness of this population, but resulted in their endogenous activation. Established tumors regressed in vaccinated mice treated with antibody against CD40 at a time when no response was achieved with vaccination alone. These results indicate that modulation of antigen-presenting cells may be a useful strategy for enhancing responsiveness to immunization.

The efficacy of therapeutic vaccination for the treatment of cancer is limited by peripheral tolerance to tumor antigens. In vivo blockade of CTLA-4, a negative regulator of T cell function, can induce the regression of established tumors and can augment the tumor rejection achieved through therapeutic vaccination. These outcomes may reflect enhanced tumorspecific T cell priming and͞or interference with the development of tolerance to tumor antigens. We examined the effect of CTLA-4 blockade on the fate and function of T cells specific for a model tumor antigen in the tumor-bearing host. We found that while CTLA-4 blockade enhanced the priming of responsive T cells, it did not prevent the induction of tolerance to tumor antigens. These results demonstrate that there is a critical window in which the combination of CTLA-4 blockade and vaccination achieves an optimal response, and they point to mechanisms other than CTLA-4 engagement in mediating peripheral T cell tolerance to tumor antigens.

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14586 Background: There are 2 monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) available for the treatment of advanced metastatic colorectal cancer- panitumumab, a fully human IgG2 kappa mAb and cetuximab, a chimeric IgG1 mAb. The ability to administer one agent after prior treatment with the other is unknown and further, not trivial given the possibility for cross-reactivity. In our institution, we evaluated an exploratory treatment schedule. Methods: We report the status of 8 colon cancer pts treated with panitumumab monotherapy as 3rd-line and subsequently treated with cetux/bev/iri as salvage chemotherapy. All were initially treated on 1 of 2 multicenter phase 2 studies enrolling pts on panitumumab; all pts had documented progressive disease (PD) during or after fluoropyrimidine and adequate doses of irinotecan and oxaliplatin, and low (1–9%) or high (=10%) EGFR tumor membrane staining by IHC. Pts received panitumumab 6 mg/kg q2weeks (wks) until PD or intolerability. Following PD they received bev 5 mg/kg and iri 250 mg/m2 q2wks and cetux 400 mg/m2, then 250 mg/m2 qwk. The endpoint was time to tumor progression (TTP). Results: The 8 pts (2 men, 6 women) were among those enrolled in 1 center. Median age was 67 years (range 51–81); 6 pts had low and 2 pts had high EGFR tumor expression. The median number of cycles of panitumumab was 8 (range 3–14); 1 had a partial remission (PR) for 24 wks, 4 had stable disease (SD) for a median of 14 wks (range 12–16) and 3 pts had PD. Following PD on panitumumab pts received cetux/bev/iri. The median number of cycles was 13 (range 2–17+); 1 had a PR of 20 wks, 6 had SD for a median of 20 wks (range 8–32+) and 1 pt had PD after 4 cycles. Median TTP was 24 wks (range 7–36+). Conclusion: In these 8 pts, prolonged TTP to the combination of cetux/bev/iri was observed following PD on panitumumab and standard chemotherapy. This combination may provide a potential treatment strategy for these heavily pretreated pts with advanced colon cancer. However, further investigation is needed. No significant financial relationships to disclose.

Lenalidomide was approved by the US Food and Drug Administration in December of 2005 for the treatment (tx) of transfusion-dependent anemia (TDA) in patients (pts) with MDS and chromosome 5q deletions (del5q). In the trial that secured the approval, 67% of 148 pts achieved red blood cell (RBC) transfusion independence (TI) with a median time to TI of 44 weeks. 90% of pts who achieved TI did so by completion of 3 months of therapy. In a companion study (MDS-002) pts lacking del5q the frequency of TI was only 26%. We report three cases of IPSS Low risk myelodysplasia MDS with a delayed response to lenalidomide. The patient characteristics are outlined in Table 1. Following a 6 to 11 month trial of lenalidomide for TDA in IPSS Low risk MDS delayed TI can occur 1 to 4 months after discontinuation of lenalidomide. Delayed TI was not associated with a cytogenetic response. The duration of response can last from 11 months to 16 months. Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. Effects of lenalidomide such as increased production of interleukin-2 and interferon-γ have been linked to the appearance of lymphoid aggregates of a mixture of B and T cells in the BM specimens of responders. TI has previously been correlated with suppression of the del5q clone. In our patients, TI was achieved after discontinuation of lenalidomide following a reasonable ineffective trial and no apparent suppression of the del5 clone. A similar phenomenon was described by Raza, et al. in a single MDS patient treated with thalidomide. Interestingly, one patient had lymphoid aggregates of B and T cells throughout treatment, raising the possibility that the immune stimulatory effects of lenalidomide may be a variable against the del5q clone. The transient response may be due to immunomodulatory effects but persistence of the del5q clone in two of our patients and and dysplasia in the other, is responsible for the relapse after the immune response has waned. Re-treatment with lenalidomide in our patient did not prolong or re-induce another response. References Giagounidis AAN, Germing U, Aul C: Biologic and prognostic significance of chromosome 5q deletions in myeloid malignancies. Clin Cancer Res 2006, 12:5–10. List A, Kurtin S, Roe DJ, et al.: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005, 352:549–557. List A: Recent advances in the treatment of MDS. Clin Advances in Hematology. Oncology. 2007, Supp 10, Vol 5, Issue 7: 4–5 Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001 Aug 15, 98(4):958–65.

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4942 Background The mechanism of lenalidomide-induced neutropenia, a common reason for cessation of therapy, has recently been shown to involve down-regulation of transcription factor PU. 1, resulting in granulocyte maturation arrest and accumulation of myeloid precursors (Pal S, et al. Blood 2010; 115(3):605–614). Data have also exhibited a correlation between cytopenias and response to therapy in del(5q) patients alone, revealing lenalidomide-induced neutropenia or thrombocytopenia as a predictor of transfusion independence (Sekeres MA, et al. J Clin Oncol 2008. 26(36):5943–5949). Because preliminary data from our phase I/II optimal dose study in non-5q- low and int-1 risk patients has shown a lower degree of both neutropenia and thrombocytopenia than that observed in patients treated with the same 10mg/d dose for del(5q) disease, we hypothesized that the comparably poor response of non-del(5q) patients may be related to the lesser degree of associated cytopenias in the setting of a suboptimal dose. Anticipating the limitation of optimal dosing by neutropenias, we set out to determine whether we could avoid withholding the drug for safety by demonstrating the patients' ability to mobilize neutrophils with corticosteroid administration, in contrast to limitation by true marrow suppression. Methods In the course of our phase I/II optimal dose study, we examined whether cytopenias observed with high dose lenalidomide may be attributed to margination rather than entirely to true marrow suppression. Eight patients with low or int-1 risk non-del(5q) MDS received lenalidomide at an increased dose of 15mg to 20mg, administered for 21d of each 28d cycle. A baseline absolute neutrophil count along with a pre-therapy response of peripheral granulocytes to prednisone was established. Patients whose absolute neutrophil count decreased during therapy to less than 50 percent of the pre-study baseline underwent a granulocyte mobilization test, receiving a 1mg/kg dose of prednisone with a complete blood count drawn both before and twenty four hours after administration to assess change in absolute neutrophil count. In patients with a positive steroid test, we proceeded with therapy. In those with a negative steroid test, lenalidomide was held until recovery of ANC. This study is listed on clinicaltrials. gov under the identifier NCT00699842. Results Of the 8 patients enrolled in the study, 4 (50%) of these patients developed neutropenia with an absolute neutrophil count (ANC) falling to less than 50% of their pre-treatment baseline. Of these patients, 2 had a marked response to the prednisone granulocyte mobilization test, with 24-hour post-steroid ANC levels approaching and in most cases exceeding the patients' baseline values (Fig. 1). A third patient had a less notable and delayed response, but did exhibit an increase in ANC from less than 50% to within 5% of pre-study baseline. The fourth patient responded minimally and was taken off of the study to receive G-CSF (Fig. 3). There was no increase in neutropenic fever during the course of the study, although the observation was limited to only 8 patients. Conclusions Determining increments of ANC (31000) following steroid administration in 3 (75%) of the studied patients who developed marked neutropenia in the setting of an elevated dose of lenalidomide demonstrated a return of the absolute neutrophil count to pre-treatment levels. The drug was continued on these patients with no neutropenic fever nor other adverse event. The results of the study provide evidence that margination of neutrophils is a contributing mechanism of lenalidomide-induced neutropenia, providing an alternative explanation to true marrow suppression as the primary etiology of observed cytopenias. This may allow for increased tolerance and determination of the optimal dose of lenalidomide in the treatment of patients with non-5q myelodysplastic syndrome. Disclosures: Besa: Celgene: Research Funding. Quan:Celgene: Employment.