Assistant Professor Govind Srimathveeravalli of the Mechanical and Industrial Engineering Department has received a $603,550 grant from the Department of Defense (DoD) to study how to redeploy macrophages to effect sustained and robust anti-tumor response in patients with bladder cancer. “The idea is to use macrophages, which are typically cells involved in housekeeping and wound healing, as a new avenue to immunotherapy of early stage and localized cancers,” says Srimathveeravalli. The project’s co-principal investigator is Ashish Kulkarni of the Chemical Engineering Department.
Srimathveeravalli adds that “We expect macrophages to succeed in patients where primary T-cell based immunotherapy failed because of their more straightforward mechanism of action, and we will test this new therapeutic approach [specifically] in bladder cancer, where local cancer recurrence is high and patients with recurrent tumor are faced with the choice of undergoing severely morbidity inducing surgery or multiple rounds of chemotherapy.”
Srimathveeravalli says that his DoD supported research is especially relevant to active-duty service members and veterans who are at high risk for developing bladder cancer due to unique environmental exposure to toxins and heavy metals, as well as other work-associated risk factors.
According to Srimathveeravalli, early stage and localized non-muscle-invasive bladder cancer (NMIBC) is the initial diagnosis in over 70 percent of all bladder cancer patients. Despite detection at an early, localized stage, durable cure of bladder cancer has proven elusive.
The standard of care is to remove the tumor with minimally invasive surgery, followed by intra-bladder administration of chemotherapy or performing T-cell-based immunotherapy using the Bacillus Calmette–Guérin (BCG) vaccine to treat widespread microscopic tumors or diseased cells present throughout the inner urothelial layer lining the bladder.
However, as Srimathveeravalli explains, “Despite their cancer being detected at an early stage, the majority of NMIBC patients will experience recurrence of tumors in their bladder and remain at elevated risk of developing aggressive, metastatic disease for the duration of the lifetime.”
Srimathveeravalli goes on to explain that “While T-cell immunotherapy has revolutionized the treatment of cancer, 40 years of clinical experience with the BCG treatment of bladder cancer and the early results from checkpoint inhibitor trials reveal a considerable rate of non-responders, the lack of durable cure, and significant treatment-related toxicity as limiting factors.”
The solution that Srimathveeravalli is exploring with his DoD grant is the use of macrophages, which are an important part of our immune system. “These cells are capable of killing cancer cells without the need for the complex series of steps and conditions that are required to initiate and sustain T-cell immunotherapy,” says Srimathveeravalli.
However, increased infiltration and presence of macrophages in the bladder, high macrophage-to-cancer cell ratio, and favorable macrophage activation status are crucial conditions that are required to enable macrophage-mediated immunotherapy of NMIBC and other malignancies.
“Our objective,” says Srimathveeravalli, “is to address the critical gap in NMIBC therapy by developing new technology for the locoregional application of ‘irreversible electroporation’ in the bladder to generate an immuno-microenvironment favorable for macrophage-mediated immunotherapy, independent of patient or tumor characteristics.”
According to Mount Sinai Hospital in New York City, irreversible electroporation “is a new technology that destroys cancerous tumors with short electrical pulses without thermal heat. The main advantage of [the technique] is that we can administer it safely to tumors that are near critical parts of your body without doing damage to healthy organs or tissue.”
Srimathveeravalli said that, following the development of his new irreversible electroporation technique, “We will combine this technique for nanoparticles developed in Professor Kulkarni’s lab to reprogram these macrophages for sustained anti-cancer effect.”
Meanwhile, Kulkarni summarized his function in the DoD proposal this way: “Our lab has designed a self-assembling supramolecular nanoparticle that targets tumor associated macrophages, immune cells that can suppress anti-tumor immunity, and inhibits a key signaling pathway. This reprograms the macrophages to anti-cancer phenotype, allowing them to engulf and digest tumor cells.”
Kulkarni added that “The DoD grant would allow us to combine these macrophage-targeted nanoparticles with the irreversible electroporation technique developed in Professor Srimathveeravalli’s lab in a novel way and for the first time study the impact of this combination on bladder cancer.”
Besides bladder cancer, Srimathveeravalli’s results will hold relevance for many other non-metastatic or early stage tumors that are not candidates for T-cell immunotherapy.
In general, Srimathveeravalli’s research group (Lab Affiliation: Srimathveeravalli Research Group) develops technology for the delivery of non-ionizing energy that enables ablation or drug delivery to tumors and healthy living tissue. (May 2020)