Immune-related response criteria

Immune-Related Response Criteria (irRC) are a set of guidelines developed to assess the efficacy of cancer immunotherapy treatments. Unlike traditional response criteria, such as the Response Evaluation Criteria in Solid Tumors (RECIST), irRC takes into account the unique patterns of response and progression observed with immunotherapeutic agents. These criteria were introduced in response to the observation that patients treated with immunotherapy may experience an initial increase in tumor size or the appearance of new lesions before showing signs of tumor shrinkage. This phenomenon, known as pseudoprogression, reflects an inflammatory response and can be misinterpreted as disease progression when using conventional response criteria.

Background

The development of irRC was motivated by the advent of immunotherapy as a promising treatment modality for various types of cancer. Immunotherapy works by enhancing the body's immune system to fight cancer cells. However, the mechanisms of action of immunotherapies differ significantly from those of traditional chemotherapies and targeted therapies, leading to different patterns of tumor response and progression. Traditional criteria like RECIST were found to be inadequate for accurately assessing the clinical benefit of immunotherapy in clinical trials, as they could prematurely categorize patients experiencing pseudoprogression as having disease progression.

Criteria

The irRC are based on the principles of measuring tumor burden and assessing changes over time, but with modifications to account for the unique response patterns seen with immunotherapy. The criteria involve a comprehensive assessment of all lesions, both measurable and non-measurable, at baseline and at subsequent time points. Key components of the irRC include:

• Total Tumor Burden: The sum of the products of the longest diameter for all target lesions, including new lesions, is used to calculate the total tumor burden.
• Response Evaluation: Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), based on changes in total tumor burden. Importantly, the appearance of new lesions does not automatically qualify as PD, as it does in RECIST.
• Pseudoprogression: A temporary increase in tumor size or the appearance of new lesions, followed by tumor size reduction or stabilization, is recognized as pseudoprogression.

Application

The irRC have been applied in clinical trials of immunotherapeutic agents, providing a more accurate assessment of their efficacy. By acknowledging pseudoprogression, irRC prevent premature discontinuation of potentially beneficial treatments. These criteria have been particularly useful in trials involving agents such as PD-1 and PD-L1 inhibitors, which have shown a tendency to induce immune-mediated tumor responses that fit the pseudoprogression pattern.

Limitations

While the irRC offer improvements over traditional criteria, they are not without limitations. The assessment of total tumor burden and the interpretation of pseudoprogression require significant expertise and can be subject to variability. Additionally, the criteria may not be applicable to all types of cancer or all immunotherapeutic agents.

Conclusion

The Immune-Related Response Criteria represent a significant advancement in the evaluation of cancer immunotherapies, addressing the unique response patterns these treatments can induce. As the field of immunotherapy continues to evolve, further refinement of these criteria may be necessary to ensure their applicability across a broader range of cancers and treatment modalities.