Do we need novel radiologic response criteria for brain tumor immunotherapy?

Early phase studies of glioma vaccines have shown encouraging preliminary clinical activity. However, as the therapeutic basis of immunotherapy involves the induction of an inflammatory response in the lesion, it is often challenging to properly evaluate radiological responses. Long-term survival and/or regression are sometimes seen after initial imaging changes that can suggest immunotherapy failure, which highlights the limitations of conventional response evaluation approaches and calls attention to the need for more therapeutically relevant strategies to provide a reliable assessment of response to brain tumor immunotherapy. As our knowledge of immunologic science has evolved [1], and novel immunomodulatory agents have become available, we have begun to face unique challenges in the radiologic evaluation of patients, given that inflammatory responses induced by vaccine strategies can mimic radiologic features of tumor progression [2]. A series of published studies of vaccination in brain tumor patients has suggested that the incidence of ‘tumor pseudoprogression’ following vaccine treatments is not insignificant, which may result in the possible unnecessary withdrawal of patients from these studies. Conversely, objective tumor regressions have been reported following postvaccine chemotherapy [3–5], which complicates the determination of whether efficacy resulted from a delayed response to the immune therapy, a direct effect of the chemotherapeutic agent, or a combination of both. In this regard, Wheeler et al. reported that vaccinated patients receiving subsequent chemotherapy exhibited significantly longer times to tumor recurrence after chemotherapy, relative to their own previous recurrence times [5]. Furthermore, they demonstrated a correlation between vaccine responses and time-to-progression (TTP) spanning chemo therapy [4]. These findings imply that the biological status of these tumors at the time of switching from immunotherapy to chemotherapy may not represent pure tumor progression, but rather an effect of vaccine-induced immune responses within the persisting tumors. Indeed, we recently reported pathological evidence of pseudoprogression in a patient who participated in our Phase I/II vaccine study using type-1 polarizing dendritic cells and a potent immunoadjuvant, polyinosinic-polycytidylic acid (poly[I:C]) stabilized by lysine and carboxymethylcellulose (poly-ICLC) [6]. Following vaccination, this patient demonstrated enlargement of the gadolinium-enhanced lesion on MRI scans, and thus underwent craniotomy. However, the resected tissue revealed no evidence of a mitotically active tumor, and remarkable infiltration of CD68 macro phages and CD8 T cells. This implies that MRI-based evaluation of TTP requires careful interpretation Hideho Okada