Summary
Combination of Ipilimumab and Nivolumab has emerged as the most effective cancer immunotherapy,
resulting in 70% of metastatic melanoma patients to achieve survival beyond three years. However, greater
than 50% of the patients developed grades 3-4 immune related adverse events (irAE). In neo-adjuvant setting,
the grades 3-4 irAE can reach 73-90%. By increasing the activity of the immune system, combination of
Ipilimumab and Nivolumab enhances the host response to inflammatory signals. Although any organ system
can be affected, irAEs most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less
often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems
are involved. It has been recognized that IrAE is a major bottleneck in cancer immunotherapy: irAEs not only
are major threats to patient survival and wellbeing, but also limit the dosing amount and schedule thus reduce
the efficacy of cancer immunotherapy. Therefore, novel approach is urgently needed to combat irAE. No
prospective trials have defined strategies for effectively managing specific irAEs and the clinical practice
remains variable. Here we propose that prevention of irAEs is the best management approach.
Danger-associated molecular patterns (DAMPs) are released when tumor cells killed by the host immune
system. Accumulating data suggested that innate responses to DAMPs may lead to immune-mediated
destruction to host tissues. Since CD24-Siglec G/10 interaction has been shown to dampen response to
DAMPs, we hypothesize that fostering activation of Siglec 10 by CD24Fc may reduce irAE among
patients receiving Ipilimumab and Nivolumab combination therapy. In support of this hypothesis, we
have established a mouse model that fully recapitulate human irAE. We have further demonstrated that
CD24Fc effectively reduce severe irAE while enhancing immunotherapeutic effect of Ipilimumab+anti-mouse
PD-1.
Based on these exciting data, we proposed a phase II clinical trial called CINDI (Combine CD24Fc to
Ipilimumab and Nivolumab to Decrease irAE). Since we have obtained proof-of-concept data both for the
fundamental concept and for biological activity of CD24Fc in human diseases, we proposed a fast track phase
I/II SBIR grant to clinically test our novel hypothesis. Phase I SBIR will achieve the goal to submit IND
application and to establish infrastructure required for the CINDI trial. Phase II SBIR will use a fixed dose of
CD24Fc to explore the safety and efficacy of combining CD24Fc with ipilimumab and nivolumab to reduce the
toxicity of this combination without affecting cancer immunotherapy effects.
Our proposed studies represent a new paradigm for prophylaxis of irAE and thus has the potential to greatly
improve the horizon of combination immunotherapy.
