Joshua Brody, MD

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses Fas and its impact on bystander killing in patients with non-Hodgkin lymphoma.

Tumor cells that express Fas are sensitive to bystander killing, while those that don't express Fas are completely resistant to bystander killing, says Brody. To date, there’s a great deal of information available on Fas. For example, it has been discovered that, with FDA-approved small molecule inhibitors such as BCL-2, HDAC, and IAP inhibitors, Fas signaling in tumor cells can be increased, Brody explains.

Furthermore, by inhibiting Fas signaling regulators, bystander killing can be increased and antigen-negative tumor cells can be destroyed, Brody explains. Interestingly, investigators believe that the geographic targeting of antigen loss tumor cells may be a way to avoid antigen loss. This would be an extraordinarily practical and simple method, Brody says.

Furthermore, patients who were treated with CAR T-cell therapy in the ZUMA-1 trial, a single-arm, multicenter, registrational trial that was conducted at 22 sites in the USA and Israel, were more likely to respond to therapy when they had high levels of Fas in their tumors. These patients were also much more likely to survive 1 year after receiving the CD19-directed CAR T-cell therapy, Brody explains.

Numerous ongoing trials continue to show the importance of Fas signaling receptors. Investigators believe that, by modulating Fas signaling, they may be able to prevent patients with hematologic malignancies from relapsing, Brody concludes.

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Joshua Brody, MD, discusses Fas and its impact on bystander killing in patients with non-Hodgkin lymphoma.

Dr. Brody on Modulating Fas Signaling to Prevent Relapse in Hematologic Malignancies

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses addressing required resistance to immunotherapy in non-Hodgkin lymphoma.

Despite the promising data seen with in-situ vaccines in the field, it is common knowledge that patients’ tumors can become resistant to vaccines or any type of immunotherapy through antigen escape, explains Brody. With regard to CAR T-cell therapy, this can mean the loss of CD19 from the tumor. With bispecific antibodies against CD20, this can mean CD20 loss, adds Brody. With every other type of immunotherapy where T cells recognize tumors through their major histocompatibility (MHC) class 1 expression, it can be MHC class 1 loss. This has been well described for many types of cancer after a patient receives a PD-1 inhibitor. In fact, class 1 loss is one of the most common types of resistance to checkpoint inhibitors, notes Brody.

Investigators started to observe this in some of the patients with advanced-stage indolent non-Hodgkin lymphoma who had been treated with an 

. Brody and colleagues shared some data that have been developed in the lab in their attempt to address antigen escape. They found that there are many ways to solve the problem of antigen escape in CAR T-cells. After giving an anti-CD19 CAR T-cell, an anti-CD22 CAR T-cell can be given as treatment, in case the patient lost the CD19 antigen, concludes Brody.

Joshua Brody, MD, discusses addressing required resistance to immunotherapy in non-Hodgkin lymphoma.

Dr. Brody on Addressing Acquired Resistance to Immunotherapy in Non-Hodgkin Lymphoma

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses the role of immunotherapy in indolent lymphomas.

The armamentarium in non-Hodgkin lymphoma includes several treatment modalities, such as chemotherapy, antibody-based therapy, small molecule inhibitors, BCL-2 inhibitors, BTK inhibitors, and PI3K inhibitors, says Brody.

However, identifying active immunotherapy options has been challenging in this space, explains Brody. For example, PD-1 inhibitors, which have significant activity in melanoma, lung cancer, and Hodgkin lymphoma, have not shown the same efficacy in indolent lymphomas.

While bispecific antibodies have shown promising activity with high rates of durable remissions in patients with diffuse large B-cell lymphoma and low-grade lymphomas, treatment with bispecific antibodies may result in antigen loss. Addressing this escape mechanism will be an important clinical challenge to address, concludes Brody.

Joshua Brody, MD, discusses the role of immunotherapy in indolent lymphomas.

Dr. Brody on the Role of Immunotherapy in Indolent Lymphomas

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses the utility of in-situ vaccines as a novel way to harness immune response and extend the reach of immunotherapy in patients with advanced-stage indolent non-Hodgkin lymphoma.

Similar to preventive vaccines, the therapeutic vaccine has proved to be safe, says Brody. Some patients who receive these therapeutic vaccines develop transient fevers that last about 1 day. However, if patients take acetaminophen and drink fluids, the fevers are transient, even in those who experience high fevers, adds Brody. Most fevers took place after 1 of the injections rather than throughout the time they were administered.

To date, no patients have developed any autoimmune-like adverse event (AE), which is often a concern with other immunotherapies, mostly with checkpoint inhibitors where autoimmune-like colitis, dermatitis, hepatitis, and pneumonitis can occur, according to Brody. Notably, those AEs have not been reported with the vaccine approach. Other inflammatory-like immune AEs that are typically seen with CAR T-cell therapy, such as cytokine release syndrome or neurotoxicity, have not been observed with this approach either. Overall, the therapeutic vaccine has been safe, concludes Brody.

Joshua Brody, MD, discusses the utility of in-situ vaccines as a novel way to harness immune response and extend the reach of immunotherapy in patients with advanced-stage indolent non-Hodgkin lymphoma.

Author | Joshua Brody, MD

Articles

Dr. Brody on Modulating Fas Signaling to Prevent Relapse in Hematologic Malignancies

Dr. Brody on Addressing Acquired Resistance to Immunotherapy in Non-Hodgkin Lymphoma

Dr. Brody on the Role of Immunotherapy in Indolent Lymphomas

Dr. Brody on Tolerability of In-Situ Vaccines in Indolent Non-Hodgkin Lymphoma