Optimizing mechanisms for induction of immunogenic cell death to improve clinical outcome in high risk multiple myeloma patients
Dana-Farber Cancer Institute
Project Term: July 1, 2019 - June 3, 2022
Immune evasion drives myeloma progression and hampers a long-term clinical response. We are using functional studies and genomic profiling to characterize the specific gene alterations driving tumor immune escape. We are also developing therapeutic combinations to stimulate the patient’s immune system against their own myeloma. Overall, this study will provide proof-of-concept for the rapid clinical translation of novel therapeutic approaches to improve the outcome of myeloma patients.
Multiple myeloma (MM) is a complex heterogeneous malignancy of mature B cells that accounts for almost 10% of all hematologic malignancies. In recent decades, the introduction of novel therapies have led to improved rates and frequency of response in MM patients, however disease relapse remains a barrier to long-term therapeutic success. Immunotherapy is showing unprecedented results in various malignancies and has begun to transform MM treatment as well. A promising approach to improve the clinical benefits for MM patients is based on the evidence that MM cells dying from specific treatment can in turn be taken up and recognized by the patient’s own immune system, thereby triggering an immune response against their own MM. This process is called immunogenic cell death (ICD) and our goal is to characterize the key molecular mechanisms underlying the induction of ICD in MM in order to harness the power of a specific anti-MM immunity. Bortezomib is one of the most durable MM treatments that both directly kills tumor cells while also triggering an immune reaction against dying MM cells (ICD). However, in some patients with high risk MM, particularly those carrying a deletion in one of their chromosomes (17p13 deletion), there is early relapse of disease in spite of bortezomib treatment. Our preliminary data show that this may be due to the lack of induction ICD triggered by bortezomib; and we hypothesize that high-risk MM cells with del(17p) may lack genes needed to turn on the ICD, thus limiting the clinical effectiveness of bortezomib treatment in these patients. We will analyze the molecular mechanisms by which ICD is triggered in bortezomib-treated MM cells. We also seek to identify the specific genes that are lost in MM patients having the 17p13 deletion that impair ICD in these patients. Finally, we will use this information to see if we can experimentally enhance ICD in laboratory models of MM and if we can restore bortezomib-induced ICD in MM models representing patients with 17p13 deletion. If we are successful, we hope to provide proof-of-concept for rapid translation of combination clinical trials to restore ICD triggered by bortezomib and improve patient outcome, even in high-risk patients with unfavorable prognosis.