Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.

We report a single center phase II trial of sequential vaccination followed with vaccine plus interleukin-2 (IL-2). Vaccination consisted of autologous cells cultured from primary tumor or resected metastasis, transduced to express B7.1 surface molecule and then irradiated. The vaccine would hypothetically costimulate tumor-reactive T cells before IL-2 exposure. Treatment plan was 3 subcutaneous vaccine injections at 4-week intervals and subcutaneous IL-2 treatment for 6 weeks starting at week 7. Sixty-six patients enrolled, of whom 39 received at least 1 vaccine; most observed toxicity was attributable to IL-2 not vaccine; best responses were 3% pathologic complete response, 5% partial response, 64% stable disease, and 28% disease progression. Median survival was 21.8 months (95% confidence interval 17.8 to 29.6). Significant postvaccination increases in IFN-gamma responses to autologous tumor were observed in 2/26 cases. Eighty-one percent of posttreatment subdermal delayed-type hypersensitivity tests (using nontransduced, irradiated autologous tumor cells) had biopsies demonstrating injection site lymphocytic infiltration. Post hoc comparison of the median survival of subjects whose biopsies had lymphocytic infiltration appears longer than in the 19% noninfiltrated (28.4 vs. 17.8 mo, P=0.045, two-sided log-rank test). The single arm design precludes conclusive comparison of objective response rates (not different here) or median survival (longer here) versus those of historical series using similar IL-2 schedules alone. Better outcomes could be logically associated to vaccine response (detectable lymphocytic infiltrates) or to random events that a single arm study design cannot address. This vaccine approach may merit further clinical development.

We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized that the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Intradermal vaccine was given q14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before the 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after the 1st and 4th vaccines to enhance dendritic cell differentiation. Twenty-four participants were accrued at a single institution from 10/2006 to 6/2008, with a median age 64 and median of 4 previous lines of systemic therapy. A total of 101 vaccines were administered. Common toxicities were headache (54%) and site reaction (38%). No radiologic responses were observed. Median overall survival (OS) was 7.9 months (mo) and median progression-free survival (PFS) was 1.7 mo. Of 14 patients evaluable for immunological study, 5 had peptide-induced CD8+ T-cell activation after vaccination. Overall, vaccine administration was feasible in an extensively pretreated population of metastatic lung cancer. Despite a suggestion of clinical activity in the subset with immune response, the trial did not meet the primary endpoint of inducing radiologic tumor regression.

CD40‐mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen‐presenting cells, namely dendritic cells (DC), by CD40L leads to maturation and up‐regulation of co‐stimulatory molecules B7.1 and B7.2 (CD80 and CD86). These molecules are requisite to subsequent antigen‐specific activation of T cells. T‐cell activation is a critical aspect of specific anti‐tumour immune responses that have become the focus of a variety of cancer immunotherapy approaches. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40, CP‐870,893, has been developed. A fully autologous mixed tumour cell/lymph node cell model was utilized to demonstrate that CP‐870,893 promotes the responsiveness of lymph node‐derived T cells to autologous tumour. Specifically, T cells from the tumour‐draining lymph nodes are not responsive to autologous tumour cells; however, in the presence of CP‐870,893, this unresponsiveness is reversed, as indicated by lymph node cell proliferation and cytokine secretion. Monocyte‐derived DC treated with CP‐870,893 consistently display a mature phenotype: up‐regulation of CD80, CD83, CD86 and HLA‐DR expression, increased Mip1α and IL‐12 secretion, and the loss of exogenous antigen‐presenting capability subsequent to treatment with the antibody. These data indicate that CP‐870,893 binds to and activates DC, ultimately driving a specific anti‐tumour T‐cell response.

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