Modulating IL-2 for Non-Hodgkins' Lymphoma (NHL)

Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003

Faculty Disclosure: Michael A. Caligiuri, M.D.
This presentation by Dr. Caligiuri discusses off-label use of IL-2 for the treatment of NHL.

Presenter: Michael A. Caligiuri, M.D.
Affiliation: James Cancer Hospital and Ohio State University

Manipulating the immune system of a non-Hodgkins' lymphoma to launch an attack on foreign tumor cells has been an ongoing area of research. The cells of interest are the body's innate immune effector cells, namely natural killer (NK) cells (also known as large granular lymphocytes) and monocytes. Both of these cell types are capable of binding tumor cells that have first been labeled with tumor antigen-specific antibodies, (eg: anti-CD20). This is the basic science behind the ever-emerging concept of antibody-dependent cellular cytotoxicity. Of note, while NK cells only express "activating" receptors that release cytotoxic granules, monocytes display both activating and inhibiting receptors. Thus, if the number of inhibitory receptors is greater than the number of activating receptors, there is a consequent undesirable reduction in the tumor lysis response.

Animal studies have provided proof of principle, demonstrating maximal clearance of implanted melanoma tumor cells following antibody administration in knockout mice lacking all inhibitory receptors. In contrast, and as expected, knockout mice lacking all activating receptors demonstrated no tumor clearance.

Attempts at maximizing the tumor lysis response of anti-tumor antibodies are thus focusing on favorably altering the balance between the two types of receptors, favoring activation rather than inhibition of tumor lysis.

One of the more promising techniques for accomplishing this altered balance is the use of interleukin 2 (IL-2) in addition to the anti-tumor antibody rituximab in patients with relapsed or refractory CD20+ NHL. The rationale behind using IL-2 stems from the fact that it is a surrogate for IL-15, which is an endogenous stimulator of NK cells. Phase I data from the NHL 01 (17 evaluable patients: weekly rituximab + daily IL-2) and NHL 02 (13 evaluable patients: weekly rituximab + 3 times/week IL-2) trials have shown promising response rates. Although the number of evaluable patients is admittedly small, the phase I data have demonstrated the feasibility of combination immune therapy in NHL patients from a safety standpoint. Furthermore, when subset analysis is performed separating responders from non-responders, a higher number of activating receptors was noted in the former group compared to the latter, thus providing elegant correlation between in vivo and in vitro data.

Now underway is a phase II/III trial (NHL 03) evaluating the combination of IL-2 and rituximab in NHL patients who have failed prior single-agent rituximab. The study design consists of rituximab 375 mg/m2 weekly x 4 cycles, with IL-2 14 MIU weekly, starting week # 2 x 8. The goals are to evaluate both response rates as well as the safety profile of this regimen. The results of this study will be vital in establishing the role of combination immunomodulatory therapy in the treatment of NHL patients.