Immunotherapy for Non-Hodgkin’s Lymphoma

Immunotherapy for Non-Hodgkin’s Lymphoma

Since 1970, when the late Dr. Jeff Gottlieb devised the CHOP regimen (cyclophosphamide [Cytoxan, Neosar]/doxorubicin/vincristine [Oncovin], prednisone) at M. D. Anderson Cancer Center,[1] no major therapeutic advances had been made in the front-line management of aggressive non-Hodgkin’s lymphoma, except perhaps in patients younger than 60 years with poor prognostic features (ie, tumor score > 2). In a phase II study from 1998, the intensive alternating triple therapy (ATT) regimen improved failure-free survival in young patients with poor prognostic features to 55% (from 20% with CHOP).[2] This trial used historical controls matched by prognostic factors based on the tumor score system; the results need to be confirmed in a phase III trial. No other hints of improvement in outcome have been achieved, particularly in patients over 60 years old with aggressive cell types (in whom intensive chemotherapy regimens are difficult to administer).

The Immunotherapy Agents

As for the indolent non-Hodgkin’s lymphomas, nihilism rather than optimism, has characterized their management. A "watch and wait" attitude has been the predominant management approach for these disorders. Even though several new and active cytotoxic chemotherapy agents have been introduced over the last 2 decades, their impact on the management of indolent non-Hodgkin’s lymphoma has not been as pronounced as the recent impact of biological therapy. Dr. Vose’s article is thus very timely.

In her excellent and exhaustive review of immunotherapy for non-Hodgkin’s lymphoma, rituximab (Rituxan) heads the list of active immunotherapy agents. However, from a historical standpoint, the first active immunotherapeutic agent against these disorders was interferon, which has been shown to improve the failure-free and overall survival of follicular indolent non-Hodgkin’s lymphomas. With the exception of studies that used either a low dose of interferon or non-doxorubicin-containing chemotherapy regimens, all others have confirmed the activity of this agent.[3-8]

Dr. Vose reviews the various types of biological agents being investigated for the management of non-Hodgkin’s lymphoma. Among these are unconjugated monoclonal antibodies such as rituximab (which is widely available throughout the world) as well as other newer investigational compounds such as the radiolabeled anti-CD20 antibodies tositumomab/iodine I 131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin). She appropriately points out that there are differences in the antitumor activity of the latter compounds, compared with rituximab, even though the basic ingredient of each agent is a monoclonal antibody against the CD20 antigen.

An intriguing fact is that when tumors become resistant to rituximab, they usually retain expression of the CD20 antigen. This highlights the fact that downregulation of this antigen is not responsible for most instances of resistance. The important role of the immune system as a mechanism of action for rituximab, including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity, has recently become clear.

Radiolabeled Antibodies

Several studies have pointed out that the most likely mechanism of resistance is the expression of the complement inhibitor CD55, and to a lesser extent CD59, both of which interfere with the complement-mediated lysis of rituximab.[9] In that sense, it is logical that the radiolabeled antibodies retain activity against tumors that have become refractory to rituximab but still express CD20. Their mechanism of action is totally different from rituximab because they are meant to serve as "guided missiles" that allow systemic radiation to be delivered directly to the tumor cells.

Although these radiolabeled antibodies are not as easy to administer as rituximab, they appear to be superior in terms of response and response duration.[10] The future might also bring us combinations of chemotherapy with radiolabeled antibodies, which might be more active than the combination of rituximab and chemotherapy.

Dr. Vose points out that rituximab is capable of producing molecular remissions, as measured by the polymerase chain reaction (PCR) technique applied to the blood and bone marrow. Paradoxically, molecular remissions can occur even in the presence of major residual tumor masses. This most likely reflects the inability of large antibody molecules to completely penetrate large tumor deposits.[11,12] Perhaps antibodies are capable of eliminating single cells from the peripheral blood and marrow compartments more efficiently than from large tumor masses. This phenomenon suggests that the combination of chemotherapy drugs and rituximab might work better because it breaks down large tumor masses, thereby making it easier for the antibody to penetrate the smaller tumor deposits.

Rituximab in Indolent Lymphomas

The activity of rituximab is not limited to the relapsed indolent lymphomas. Although US Food and Drug Administration approval was awarded exclusively for the salvage treatment of these disorders, the drug is also active as a single agent against mantle cell and large cell lymphomas, as Dr. Vose points out. When combined with CHOP, rituximab has been associated with a longer failure-free survival in patients with large cell lymphoma.

In contrast, the Dana-Farber group used a similar approach for mantle cell lymphoma but it did not translate into any benefit for this particular histologic subset. In a sense, this should not be surprising, because CHOP does not have curative potential in mantle cell lymphoma. Hyper-CVAD (cyclophosphamide/vincristine/doxorubicin [Adriamycin]/dexamethasone) is a more effective chemotherapy regimen for this cell type.[13] Recent data from M. D. Anderson, although still preliminary, suggest that rituximab in combination with Hyper-CVAD is remarkably effective in inducing complete remissions (J. Romaguera, personal communication, 2000).

Other monoclonal antibodies reviewed in this article, although still in the investigational stage (such as anti-CD22 [LymphoCide] and 131I Lym-1 [Oncolym]) are also of interest. In the future, they may spur combination antibody regimens that target different antigens.

Future Therapies

Newer immunotherapeutic approaches, such as idiotype vaccines and dendritic cells, are thoroughly discussed by Dr. Vose. These approaches are still more experimental than the monoclonal antibodies. The drawback of this approach is that a custom-made vaccine is necessary for each patient because the rationale is to elicit an immune response against the individual idiotype expressed by each lymphoma. The cost of preparing such a vaccine is calculated at $30,000, so there is no telling how this will translate into the actual market value of such therapies if they ever become available.

It is evident from Dr. Vose’s excellent review that we have entered a new era of biological therapy for non-Hodgkin’s lymphoma. The advent of biological therapy has changed the pessimism that has permeated the management of indolent lymphomas so far. The offshoot of this silent revolution will likely also include future advances in the management of other cell types such as large cell and mantle cell lymphomas.


1. Gottlieb JA, Gutterman JU, McCredie KB, et al: Chemotherapy of malignant lymphoma with Adriamycin. Cancer Res 33:3024-3028, 1973.

2. Cabanillas F, Rodriguez-Diaz Pavón J, Hagemeister F, et al: Alternating triple therapy for the treatment of intermediate grade and immunoblastic lymphoma. Ann Oncol 9:511-518, 1998.

3. Smalley RV, Andersen JW, Hawkins MJ, et al: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med 327:1336-1341, 1992.

4. Solal-Celigny P, Lepage E, Brousse N, et al: Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 329:1608-1614, 1993.

5. McLaughlin P, Cabanillas F, Hagemeister BF, et al: CHOP-Bleo plus interferon for stage IV low-grade lymphoma. Ann Oncol 4:205-211, 1993.

6. Aviles A, Duque G, Talavera A, et al: Interferon alpha 2b as maintenance therapy in low-grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 20:495-499, 1996.

7. Hagenbeek A, Carde P, Meerwaldt JH, et al: Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin’s lymphoma. J Clin Oncol 16:41-47, 1998.

8. Fisher RI, Dana BW, LeBlanc M, et al: Interferon alfa consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin’s lymphoma: Results of the Southwest Oncology Group Randomized phase III study 8809. J Clin Oncol 18:2010-2016, 2000.

9. Golay J, Zaffaroni L, Vaccari T, et al: Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 95:3900-3908, 2000.

10. Witzig B, White C, Gordon LI: Prospective randomized controlled study of Zevalin (IDEC-Y2B8) radioimmunotherapy compared to rituximab immunotherapy for B-cell NHL: Report of interim results. Blood 94:2805a, 1999.

11. Pervez S, Epenetos AA, Mooi WJ, et al: Localization of monoclonal antibody AUA1 and its F(ab’)2 fragments in human tumour xenografts: An autoradiographic and immunohistochemical study. Int J Cancer 3(suppl):23-29, 1988.

12. Yokota T, Milenic DE, Whitlow M, et al: Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res 52:3402-3408, 1992.

13. Khouri I, Romaguera J, Kantarjian H, et al: Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: An active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803-3809, 1998.

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