The Era of Immuno-Oncology: Are We There Yet?

In 2006, a wave of optimism followed the US Food and Drug Administration (FDA) approval of rituximab for the treatment of diffuse large B-cell lymphomas in combination with chemotherapy. After all, it was the first time in more than 25 years that a new therapeutic agent had improved survival in this aggressive subtype of lymphoid malignancy. In the new era of immunochemotherapy that was ushered in by rituximab, clinicians eagerly awaited the addition of more new agents to the armamentarium available for use against lymphoid malignancies.

Expectations were replaced by frustration as a relative drought of new approvals ensued, leaving those who treat these malignancies hoping for more. The last 5 years, however, have brought an abundance of new agents to the market, restoring hope for a significant change in outcomes for patients with lymphoid malignancies.

Between 2010 and 2014, the FDA issued roughly 25 new indication-specific drug approvals for agents designed to treat hematologic malignancies. These account for about 28% of all cancer drug approvals for this period-a statistic that is all the more remarkable when one considers the fact that lymphomas and leukemias accounted for less than 8% of all new cancers diagnosed in the United States in 2014.[1]

In this issue of ONCOLOGY, Dr. Siddiqi and Dr. Rosen elegantly summarize the data on the monoclonal antibodies approved by the FDA for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia over the last 5 years.[2] These new agents bring to the table an array of new treatment strategies. Some have refined ways of attacking old targets. Others have innovated by finding clever ways to deliver cytotoxins intracellularly. A third group engages the host’s adaptive immune system in the fight against the malignant clone.

Old targets, new tricks

Antibody-directed cellular cytotoxicity (ADCC) and phagocytosis constitute the core mechanisms by which anti-CD20 therapy induces cell death in lymphoid malignancies. In contrast with chimeric rituximab, ofatumumab and obinutuzumab are novel humanized anti-CD20 monoclonal antibodies. Decreasing murine content to a minimum critical amount allows these next-generation monoclonal antibodies to curb immunogenicity to mouse sequences. Preclinical studies indicated that these new agents carry enhanced cell-killing properties compared with rituximab.[3,4]

The clinical studies of ofatumumab and obinutuzumab have been nicely summarized by our colleagues in their review. Improving on the foundation laid by rituximab is proving to be as much of an opportunity as it is a challenge. Several ongoing trials combining next-generation anti-CD20 monoclonal antibodies with standard and novel therapies are actively accruing.

While some researchers concentrated on improving the effectiveness of anti-CD20 targeting, others chose to enhance ADCC by focusing on a different surface marker. The early clinical data on epratuzumab, a humanized anti-CD22 monoclonal antibody, were encouraging, especially in combination with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).[5] However, while the agent was initially promising, the concurrent emergence of other agents with greater efficacy led to a loss of enthusiasm for further development of treatment strategies incorporating epratuzumab.

Antibody-drug conjugates: Have we found our magic bullets?

Delivering potent cytotoxins to the interior of malignant cells while sparing normal tissues the untoward adverse effects of these cytotoxics is truly the “magic bullet” of cancer treatment. This epitome of targeted therapy, a concept that can allegedly be traced back more than a century to German physician Paul Ehrlich, has never felt so real. Monoclonal antibodies have proven to be the ideal vehicle for such specific delivery. It was not until recently, however, that technological advances in their design and production made it possible to use monoclonal antibodies to target cancer cells in innovative ways.

Inotuzumab ozogamicin and brentuximab vedotin are representatives of this new class of agents, known as antibody-drug conjugates. While the first targets CD20 and the latter binds to CD30, both effectively deliver toxins to malignant cells intracellularly. Their clinical activity has been clearly demonstrated in proof-of-concept studies. A number of clinical trials are actively investigating the role of antibody-drug conjugates in the treatment in many different hematologic malignancies.

New strategies-focusing on the soil

Evading a host’s immune system to allow malignant clones to perpetuate unopposed may be one of cancer’s most critical evolutionary steps. Agents such as ipilimumab, pembrolizumab, nivolumab, and blinatumomab-not to mention completely revolutionary strategies such as chimeric antigen receptor therapy-make it easy to understand why cancer immunotherapy rightfully deserved Science magazine’s designation as Breakthrough of the Year in 2013.[6]

The clever design of blinatumomab, an antibody with dual specificity for CD19 and CD3, allows cytotoxic T cells to effectively kill B-cell clones. The seminal work led by Bargou[7] and Topp[8,9] demonstrated the clinical efficacy of this novel treatment strategy in the management of relapsed/refractory non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia patients, respectively.

While the focus of immunotherapy has been on T-cell signaling, it is important not to lose sight of other factors present in the tumor microenvironment. The approval of siltuximab, a chimeric monoclonal antibody targeting interleukin-6, reminds us of the importance of cell signaling in determining the outcomes of tumor-host interactions.

Conclusions, prospects

With new hope come new challenges. As we watch the arrival of this new group of agents, each new answer unfolds into several questions. How can we best determine the comparative efficacy of these new agents? How can these new agents and new treatment strategies be best incorporated into approaches that include the currently available options? How will the cost of these new therapies influence their use in the rapidly changing healthcare delivery system? How do we protect ourselves from the risks of accelerated approvals and limited safety data when our patients plead for new and better options?

The next few years hold great promise, as new agents emerge and others consolidate their place on our shelves. We will be forced to rethink strategies and redefine management as a new era of immuno-oncology dawns. Indeed, there are many challenges-but they are among the best kind.

Financial Disclosure:Dr. Ansell receives research funding from Seattle Genetics, Bristol-Myers Squibb, and Celldex, Inc. Dr. Villasboas has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.

2. Siddiqi T, Rosen ST. Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Part 1: monoclonal antibodies. Oncology (Williston Park). 2015;29:198-203.

3. Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793-800.

4. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031-42.

5. Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011;118:4053-61.

6. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432-3.

7. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974-7.

8. Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32:4134-40.

9. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2014 Dec 16. [Epub ahead of print]