An increasingly important question in medical oncology is how to time immunotherapy initiation with other available treatments, including surgery, radiation, and chemotherapy. The effectiveness of one treatment can depend on the effectiveness of another, making timing and flexibility critical for successful clinical care. One study published recently showed that epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are more effective after stereotactic radiosurgery for treating lung cancer brain metastases than prior drugs.1 Another study evaluating the rotation of pazopanib and everolimus for patients with metastatic renal cell carcinoma did not live up to clinical promise.2 The reasons for the results of both studies are, however, not well understood.

The authors of a recent review published in Expert Opinion on Biological Therapy claim that suppression of the immune system is relative to tumor stage.3 They note that in “…late stages the tumor micro-milieu may frustrate the effector arm of the immune system through different mechanisms.” A particular immunotherapy is therefore more likely to fail if the disease is more advanced, causing immune suppression, and it’s not surprising that immunotherapies fail sooner when surgery to reduce tumor size is performed later. Yet it is unclear whether this is always true, and how this information can be of practical benefit to oncologists and patients.

Some studies were successful in improving outcomes for patients through vaccination when there was minimal residual disease. A human papillomavirus (HPV)-synthetic long-peptide vaccine, for example, induced T cell responses among 20 of 20 patients with high-grade vulvar intraepithelial neoplasia.4 This method may, however, be less effective in patients with recurrent cancers that are vaccinated, supporting the notion that immune-mediated response is weaker at advanced disease stages.5 Other research showed that chemotherapy actually improves the efficacy of some immune cells through cytokine expression induction, suggesting that immunotherapy can be used synergistically if the mechanisms of both treatments are better understood.6

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The importance of timing is grounded on the notion that, among different tumors, varying mechanisms of immune suppression are possible, the alleviation of which requires different methods. The HPV-specific vaccine was particularly efficacious when administered within 2 weeks post-cycle 2 of platinum chemotherapy in patients suffering from tumor-associated myeloid cell suppression, whereas it is suggested that vaccination 3 to 7 days post-cyclophosphamide is optimal when regulatory T cells suppress tumor immunity.7 Immunotherapy would ideally be started the first day post-surgery to minimize tumor immunosuppression. Authors of a recent sarcoma study noted that, though their study of dendritic cell–based immunotherapy among patients with relapsed disease did not meet expectations, the treatment may be successful if administered prior to relapse, before the cancer cells are dominant enough to suppress T cell activity.8

One poorly-understood variable that may mitigate the efficacy of any testable regimens, however, is drug resistance. “There are many different ways by which tumor cells can become ‘resistant,’ said Dr S.H. van der Burg, head of experimental cancer immunology and therapy at the Leiden University Medical Center in the Netherlands. “They could upregulate different intrinsic mechanisms that protect them against immune cell–induced cell death or against immune mediated–stops in cell proliferation and division. They may also upregulate the expression of certain proteins at the cell surface, which provide a ‘stop’ signal to the attacking immune cell.”