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Could stem cell transplants make BMS’ checkpoint inhibitors work in resistant lymphoma?

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opdivo
A phase 1/2 trial combining Bristol-Myers Squibb’s immuno-oncology drugs Opdivo and Yervoy with stem cell transplants in resistant non-Hodgkin lymphoma has started enrolling patients. (Bristol-Myers Squibb)

Immune checkpoint inhibitors that release cancer cells’ brake on the immune system have proven effective in multiple cancer types, but not so much in treatment-resistant non-Hodgkin lymphoma (NHL).

Now, scientists at the Icahn School of Medicine at Mount Sinai have found a possible way to make immune-oncology agents work better for these tough-to-treat blood cancers, and it involves a well-established treatment for NHL: the transplant of blood-forming stem cells.

Adding anti-PD-1 and anti-CTLA-4 dual inhibitors to bone marrow transplants significantly increased anti-tumor immune responses, leading to durable tumor regressions in lymphoma and solid tumors in mouse models, the researchers have found. They published the results in the journal Cancer Discovery.

Mount Sinai’s immunotransplant approach is now being tested in patients with relapsed or refractory diffuse large B-cell lymphoma—the most common type of NHL—who were previously deemed ineligible for autologous stem cell transplant. The phase 1/2 uses Bristol-Myers Squibb’s approved immuno-oncology drugs Opdivo and Yervoy and has been enrolling patients since May. Opdivo as a monotherapy previously failed to move the needle in a phase 2 in the same patient population.

When it comes to treating relapsed or refractory NHL, autologous bone marrow transplant often works with high-dose chemotherapy in a process known as lymphodepletion. Stem cells are collected from a patient, and then high doses of chemotherapy are used to clear out the patient’s original immune system. This allows T cells, when given back, to proliferate in the patient’s body.

But the Mount Sinai researchers found that during the process, immune checkpoint molecules that dampen immune responses including CTLA-4 and PD-1 increased. They further confirmed that the high checkpoint expression suppressed T-cell functioning.

So it was only natural to hypothesize that PD-1 and CTLA-4 inhibitors could offset this effect. Joshua Brody and colleagues at Mount Sinai put the theory to test in a mouse model of lymphoma.

They found that antigen-specific CD8 T-cell activation was significantly greater in the transplant-double checkpoint blockade group than in mice receiving either transplant or immunotherapies alone. What’s more, durable tumor suppression was only achieved in 10% of mice that got solo regimens, while 40% on the combo drugs lived without evidence of disease after 60 days, the team reported.

Scientists have been trying various combinations of drugs to achieve better results in cancer treatment. Recently, a team also led by Brody developed an approach that delivers a vaccine consisting of two drugs directly to tumor sites to guide T cells to kill cancer. When paired with a PD-1 inhibitor, 80% of tested mice had durable remissions. A regimen that combines Roche’s CD20-targeting antibody Rituxan and a Stanford University-developed CD37-targeting drug previously achieved an objective response in 11 of 22 patients with relapsed or refractory NHL in a small study.

Brody and colleagues hope the method could work in other tumor types. In their study, the two-pronged attack also yielded durable remissions of tumors in mouse models of lymphoma, melanoma and squamous cell lung cancer.

“Using immunotransplant to enhance the efficacy of checkpoint blockade therapy could be broadly significant as these immunotherapies are a standard therapy for melanoma, kidney cancer, lung cancer, and others,” Brody said in a statement. “Even for settings in which checkpoint blockade therapy proves ineffective, our data suggest that its efficacy may be ‘rescued’ by immunotransplant. This research also suggests that the addition of checkpoint blockade may improve other T cell therapies, such as CAR-T therapy.”

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