Executive Summary

A common toxicity of advanced IO therapies, cytokine release syndrome needs to be better characterized as part of the groundwork for future development of the field, according to Friends of Cancer Research.

The products may be exquisitely personalized, but advancement of new cancer immunotherapies and cell therapies requires standardizing terms – starting with cytokine release syndrome (CRS).

The Friends of Cancer Research is drawing attention to the importance of CRS, one of the most common toxicities of chimeric antigen receptor (CAR) T-cells, to the future development of emerging immunotherapies and cell therapies, through a recent white paper and webinar. The white paper was produced by a working group that included members from US Food and Drug Administration, the US National Cancer Institute, Amgen, Inc., Genentech, Inc., Regeneron Pharmaceuticals, Inc., Kite Pharma, Inc. (Gilead Sciences, Inc.), the Medical College of Wisconsin, and Xencor, Inc.

The working group focused on the “urgent need to harmonize grading, collecting and reporting CRS” as a fundamental step toward development of the IO field. The white paper offers “a development model” to inform clinical programs, Genentech executive group medical director, clinical safety Bruce McCall told the FOCR webinar.

A Growing Field

National Cancer Institute director Ned Sharpless highlighted the many ways in which the IO field is advancing rapidly, especially in hard-to-treat cancers like melanoma and lung cancer – the payoff of a decade of research on the immune system and cancer.

Nonetheless, he observed, the field is in “many ways still in infancy,” with open questions around how to target agents and how to mitigate adverse events.

Amgen VP global development and therapeutic area head of hematology PK Morrow was more generous, placing the IO field “in adolescence,” but noted difficulty of comparing safety data across programs. Genentech’s McCall reported that of the four CAR-T therapies approved, three different CRS rating scales were used.

FDA Center for Biologics Evaluation Research Director Peter Marks looked at CAR-T IND applications to illustrate the growth of advanced immunotherapies, pointing to the 20 INDs submitted in 2015 and the 58 INDs from last year. “More are in Phase II or III,” he observed, with “real maturation” in manufacturing processes.

While the early CAR-T therapies are autologous products, Marks said that allogeneic cell therapies are now coming into IND-stage development. “In the past year or two, allo T cells have come into play for solid tumors,” he said. The first wave of autologous CAR-T has been aimed at hematologic cancers.

Evolution Of CRS As A Concept

“Transformational advances in cancer immunotherapies have brought awareness of novel toxicities like CRS,” McCall said. While the incidence of CRS is relatively low for conventional monoclonal antibodies, the issue was “unmasked” with the development of T-cell engager bispecifics. The white paper notes that there is a CRS incidence of 17% to 94% with CAR-T and T-cell engagers.

The paper describes CRS as “a supraphysiologic response driven by the immune system” that is “T-cell mediated and can occur within several hours to days after infusion, but rarely presents beyond 14 days after initiation of therapy.” The syndrome “can be short lived, but often lasts for several days.”

“Early in the development of immunotherapies, the term CRS was used more generally to describe a syndrome with a dramatic presentation requiring intensive care,” the paper states, but “it has been increasingly recognized that CRS presents with a spectrum of severities, ranging from a self-limited low grade fever to serious multiorgan collapse.”

The paper emphasizes the need to distinguish CRS from other clinical concepts, particularly acute infusion-related reactions (IRR). The broad set of AEs under the IRR umbrella “have been long defined, diagnosed, and reported in an ambiguous and inconsistent manner,” the authors state, resulting in an operational definition that encompasses “a wide array of symptoms with potentially disparate pathophysiology whose main commonality is occurrence within 24 hours of infusion.”

“Infusion-related reactions following CAR T-cell administration are infrequent and generally mild,” the white paper reports. “However, with the emergence of T-cell-engaging therapeutics, in particular T-cell engagers and fusion proteins, distinguishing CRS from IRR has been a challenge.” With the T-cell engaging therapies, acute IRRs and CRS may overlap but “likely have different pathophysiology and treatments with different prognoses.”

“Inconsistent or inadequate characterization of these toxicities in clinical trials impact how data are presented in publications and prescribing information, potentially resulting in suboptimal description and management of these clinical events,” the white paper declared. “This can put patients at risk if their treatment side effects are not properly managed.”

Data Consistency

At the FOCR event, Morrow remarked how “very far” the field has come in the evolution of response criteria for efficacy evaluation. Now development must face the other side of the coin, she said: a shared understanding of toxicity.

“Consistency in data collection is key,” FDA Oncology Center of Excellence acting associate director for safety Meredith Chuk said. “Data elements are needed in this space.” Similar data elements across trials can inform labeling and allow providers to have consistent conversations with patients, she observed.

The white paper calls for “collection of common data elements within and across development programs,” including “utilization of a harmonized definition and grading scale.”

“Establishing core principles for defining CRS that consider the therapeutic modality, symptom manifestation, timing, and response to intervention will be important to enable flexibility and maximize utility of a harmonized definition for CRS to adequately assess safety profiles of therapeutics,” the paper continues.

Then, “as more data are collected in a harmonized fashion, the field can better decide at which point and with which factors an event is determined to be a high-grade IRR versus a low-grade CRS.”

Flexibility For The Future

“Given the likely evolution of defining and grading CRS in the field, the medical community should ensure that the appropriate data elements are collected to allow derivation with different grading systems,” the white paper advises. “Collection of common data variables using aligned protocols will be important to enable comparison with different therapies in the future.”

For example, the paper notes that clinical signs and symptoms are likely to drive most diagnosis of CRS. “However, the collection of certain data variables, such as laboratory assessments, cytokine profiles, and biomarkers will be important for future retrospective analyses.”

“New agents are coming, with additional elements that may be incorporated into CRS,” Marcelo Pasquini, Medical College of Wisconsin, said. A harmonized definition of the main criteria should create a “stepping stone” for analysis in the future, so the industry doesn’t need to “reinvent the wheel every time there is a new product.”

“It is vital for us to collect data that is granular enough to allow us to pivot and adapt our evolving understanding of toxicities, especially for IO therapies,” Morrow said.

Ultimately, Chuk said she sees “data-driven development of mitigation strategies” that could be tailored based on response and toxicity parameters. The goal, she said, is “predictive models.”

The white paper acknowledges that “the collection of a broad dataset for characterizing CRS is resource intensive for both sponsors and investigators.” However, the paper advises, “assessing the risk of an IRR or CRS during preclinical and early clinical development of a new therapy will help assess the robustness of data collection required during clinical development.”

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