Immunotherapy offers great promise in treating advanced cancers that do not respond to traditional treatments. To maximize the potential of the immune system via immunotherapy, however, clinicians must be able to reliably determine how a patient’s tumors are responding to treatment.
To that end, the Cancer Research Institute (CRI) recently partnered with the Lymphoma Research Foundation (LRF) to host a workshop focused on immunotherapy evaluation guidelines for lymphoma. This workshop, CRI’s latest effort through its Cancer Immunotherapy Consortium to improve the immunotherapy-focused clinical development paradigm, brought together medical, industry, and regulatory experts to address these considerations.
When treating tumors with conventional chemotherapy, initial, often rapid reductions in tumor size indicate a positive response, and correlate with remission and survival. Conversely, increased tumor size and appearance of new lesions indicate treatment resistance and progressive disease (PD).
When treating tumors with immunotherapy, however, early tumor growth and the initial appearance of new lesions—sometimes referred to as tumor “flares”—do not always indicate true PD, but may instead be characteristic of a beneficial anti-tumor immune response. In a number of immunotherapy patients, increased tumor volume and tumor “flares” were transient phenomena that later gave way to responses or remission.
There are two reasons for this. First, because immunotherapy acts indirectly on cancer through the immune system, responses can take longer than with chemotherapy, which directly targets tumors. This allows cancers to continue growing before the immune system begins its bombardment. On the other hand, increased tumor volume and tumor “flares” may not be due to cancer cell growth, but rather the result of inflammation from immune cell infiltration that is associated with successful immunotherapy responses.
Immunotherapy Response Guidelines
Unfortunately, the current World Health Organization (WHO) evaluation guidelines reflect the nature of chemotherapy responses, but not the complex, non-linear, and longer-term nature of immunotherapy responses. For instance, new lesions—whether measureable or not—are always categorized as PD under the current standards, but may not represent true PD in the context of immunotherapy. However, the PD designation usually leads to patients being removed from treatment cycles, potentially prematurely, before immunotherapy’s full benefits can be realized.
To fix this, Jedd Wolchok, M.D., Ph.D., associate director of CRI’s Scientific Advisory Council (SAC) and the organization’s clinical program director, and Alex Hoos, M.D., Ph.D., co-chair of CRI’s Cancer Immunotherapy Consortium and also a member of the SAC, and colleagues proposed in 2009 a novel protocol for evaluating solid tumors responses to immunotherapy.
The new standard, known as immune-related Response Criteria (irRC), addresses the often-delayed effects of immunotherapy, and enables clinicians to better characterize immunotherapy responses in solid tumors. The transferability of irRC to the conventional WHO and Response Evaluation Criteria in Solid Tumours (RECIST) frameworks enables consistency between studies and eases adoption of the new irRC standards by oncologists already familiar with these protocols. Building on these ideas, the goal of this workshop was to adapt these irRC guidelines to lymphoma.
This confirmation from initial data will then pave the way for the appropriate design and analysis of the large-scale studies that will inform future immunotherapy research and treatments, and ultimately help us progress toward the goal of harnessing the immune system’s power to treat lymphoma.
Evaluation of Immunotherapy Responses in Lymphoma
In contrast to solid tumors, lymphoma forms tumors that are harder to characterize and evaluate accurately using needle-core biopsies. Instead, excisional biopsies are typically performed, despite the fact that they require removal of the entire lesion and are more traumatic, less cost-effective, and often less well-tolerated. This presents challenges for the accurate analysis and prediction of immunotherapy responses in lymphoma tumors.
Thus, standardizing the evaluation guidelines—with respect to issues such as when patients should be analyzed, how diagnostic conclusions should be formed, and how those conclusions should influence subsequent decisions regarding further treatment—will enable clinicians to improve treatments.
Additionally, much is still unknown about lymphoma tumor immunology. While tumor size serves as a suitable proxy for chemotherapy treatment response, the composition of tumors and lesions might provide better metrics and predictors of response for immunotherapy-treated tumors. However, as mentioned before, gathering useful information on lymphoma tumors remains difficult. As a result, workshop participants acknowledged the potential benefit that new analytical methods might provide, and plan to develop complementary strategies along this avenue as well.
Overall, this workshop sought to lay the important initial foundations for how these issues will be addressed. Accomplishing this first goal—consolidating the different perspectives and potential solutions and laying out the considerations in concrete terms—will enable researchers and clinicians to move forward with developing a standardized criteria for effectively evaluating immunotherapy responses in lymphoma.
The next step is to produce a white paper that outlines these considerations for a new, improved framework for lymphoma immunotherapy treatment, which could then be used in conjunction with forthcoming data to validate the criteria’s usefulness. This confirmation from initial data will then pave the way for the appropriate design and analysis of the large-scale studies that will inform future immunotherapy research and treatments, and ultimately help us progress toward the goal of harnessing the immune system’s power to treat lymphoma.
For more information on irRC, please refer to Drs. Hoos and Wolchok’s original article published in Clinical Cancer Research.