Improving the chance of cure of follicular lymphoma by combining immunotherapy and radioimmunotherapy based on anti-CD20 antibodies?

The recently published ESMO lymphoma treatment guidelines [1] recommend the use of single-agent rituximab as an option in follicular lymphoma (FL) for avoiding the side-effects of chemotherapy. We may add to this point that results from the literature as well as our own observation show that radiolabeled anti-CD20 radioimmunotherapy (RIT), as a treatment consisting of two injections given at a 7-day interval, can lead to high rates of complete responses (CRs) and over 10 years recurrence-free survival in a significant percentage of patients. These results, confirmed at the molecular level in a high percentage of cases, were observed with treatment at first line, in consolidation and in relapsed/refractory indolent lymphoma [2–4]. They favorably compare with the above-mentioned results of single-agent rituximab [1] shown to induce long-term remissions of FL and to represent a well-tolerated maintenance therapy [5]. Surprisingly, these two very efficient forms of B cell-specific anti-CD20-mediated therapies have never been tested in combination in a well-designed clinical trial of FL. In the most recent randomized, phase III trial of untreated FL, RIT, and rituximab treatments were compared, but they were both associated with the same combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy [6]. The two arms gave excellent and similar results, but the two antibody-mediated therapies could not be evaluated individually or in combination. The combination of these two forms of anti-CD20 immunotherapies might increase the CR with less side-effects than chemotherapy and preserve the T cells’ immune defenses. Indeed, the positive role of T cells’ responses against lymphomas has been well documented in experimental and clinical investigations, including idiotype vaccination and allogeneic bone marrow transplantation [7]. Furthermore, the fact that the two approved anti-CD20 antibodies, tositumomab and ibritumomab, are of murine origin includes tumor targeting of new antigens, which can be recognized in their processed form by the patient’s T lymphocytes [8]. The important role of effector cells from innate immunity, such as natural killer (NK) cells, is well known both for antibodydependent cell mediated cytotoxicity and for the prevention of recurrence. Interestingly, it was recently shown that injection of rituximab resulted in the activation of the NK cells in patients with the high-affinity Fcγ receptor genetic polymorphism [9]. The strong efficacy of RIT cannot be entirely explained by the relatively low radiation dose to the tumor cells or by the associated administration of unlabeled anti-CD20 antibody, but probably by the combination of both that associate with the patient’s preserved T cells immunity. It has been recently reported that irradiated lymphoma cells have an increased immunogenicity and that irradiation of lymphoma, accompanied by systemic delivery of a TLR7 agonist, can induce durable antitumor immune response in murine syngeneic lymphoma models [10]. In conclusion, we think that in FL the combination of these two antibody-mediated biotherapies might produce a synergy leading to higher CRs and longer disease-free survival rates than each single modality and, thanks to the preservation of the patient’s immune system, improve the chance of cure.