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

Notably, patients with Hodgkin lymphoma are more responsive to immunotherapy than patients with other tumor types, says Brody. Randomized phase 3 data have led to the approvals of multiple anti–PD-1 agents in Hodgkin lymphoma based on superior efficacy findings compared with other standards, such as antibody-drug conjugates, Brody says.

Moreover, the response rates for PD-1 inhibitors in patients with chemotherapy-refractory Hodgkin lymphoma are around 70%, with most patients achieving complete responses or durable remissions. Five years ago, many patients had to adjust their daily schedule to undergo chemotherapy, with limited curative potential. Moreover, many of these patients would go on to receive a stem cell transplant and develop progressive disease after. The introduction of PD-1 inhibitors has largely improved the burden of therapy for these patients.

Ultimately, with this new therapy, patients can achieve more durable responses, even in the refractory setting. As such, the field is looking to expand the utility of immunotherapy into earlier lines of therapy or into the maintenance setting, Brody concludes.

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Joshua Brody, MD, discusses the role of immunotherapy in Hodgkin lymphoma. 


Dr. Brody on the Role of Immunotherapy in Hodgkin Lymphoma 

Joshua Brody, MD, director of the Lymphoma program at Icahn School of Medicine, Mount Sinai Hospital, discusses the expanding role of venetoclax (Venclexta) in mantle cell lymphoma (MCL).

Venetoclax, a BCL-2 inhibitor, as a single agent or in combination with obinutuzumab (Gazyva) currently has FDA approvals in chronic lymphocytic leukemia and acute myeloid leukemia, says Brody. In MCL, venetoclax appears to be a promising emerging agent for patients with BTK inhibitor–refractory and –naïve disease.

Data with venetoclax have shown high overall and complete response rates with durable remissions in patients with MCL, Brody says. Additionally, the toxicity profile of venetoclax in MCL appears similar to what has been observed in CLL, explains Brody. Regarding safety, venetoclax poses an early risk of tumor lysis syndrome; however, the risk appears to be manageable with standard dose titration.


Overall, it is difficult to predict which B-cell malignancies venetoclax will have activity in, says Brody. However, as BCL-2 is widely expressed in MCL, there is rationale to evaluate the agent in this space, concludes Brody.

Joshua Brody, MD, discusses the expanding role of venetoclax in mantle cell lymphoma.  



Dr. Brody on the Expanding Role of Venetoclax in MCL

Joshua Brody, MD, director of the Lymphoma program at Icahn School of Medicine, Mount Sinai Hospital, discusses management strategies for the toxicities associated with CAR T-cell therapy in mantle cell lymphoma (MCL). 

Cytokine release syndrome (CRS) and neurotoxicity are adverse effects associated with CAR T-cell therapy that can be managed through conservative therapy, observation, fluid hydration, and pressor drugs, Brody explains. Patients with severe CRS can receive steroids and tocilizumab (Actemra), an interleukin (IL)-6 receptor antibody. Novel therapies, such as the IL-1 receptor antagonist anakinra (Kineret), have also demonstrated efficacy in this setting. 

Patients who develop neurotoxicity are treated with a similar strategy, says Brody, though he notes that the management protocol for CRS is further along than that of neurotoxicity. 

Managing the risk of CRS and neurotoxicity before a patient begins treatment with CAR T-cell therapy is important, says Brody. Moreover, moving CAR T-cell therapy earlier in treatment to the third-line setting could be another option, as tumor bulk plays a key role in toxicity development. Debulking patients with effective therapies prior to CAR T-cell therapy may be key to utilizing the modalities earlier, concludes Brody.

Joshua Brody, MD, discusses management strategies for the toxicities associated with CAR T-cell therapy in mantle cell lymphoma.  


Dr. Brody on Managing CAR T-Cell Therapy Toxicities in MCL 

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses the potential role for bispecific antibodies in mantle cell lymphoma (MCL).

Bispecific antibodies have emerged as a promising treatment modality for patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, Brody says. However, little data have demonstrated the utility of bispecific antibodies in MCL. Despite this, it is likely that efficacy and safety data from the DLBCL and follicular lymphoma experiences can be extrapolated to the MCL space, explains Brody.

MCL is more sensitive to CD20-directed therapy, such as rituximab (Rituxan), compared with other non-Hodgkin lymphoma subtypes, Brody says. In MCL, maintenance rituximab has demonstrated an overall survival benefit, and even rituximab monotherapy can elicit good responses. As such, it is highly likely that bispecific antibodies will be effective in MCL, Brody says. 

Moreover, the agents are currently being evaluated in combination regimens for patients who progress on standard frontline therapies, such as R-CHOP, bendamustine/rituximab, and rituximab/lenalidomide (Revlimid), concludes Brody.

Joshua Brody, MD, discusses the potential role for bispecific antibodies in mantle cell lymphoma.  



Dr. Brody on the Potential Role for Bispecific Antibodies in MCL 

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses the challenges of mitigating antigen escape in mantle cell lymphoma (MCL).

Antigen escape with CAR T-cell therapy is a common mechanism of resistance that causes the loss or downregulation of the target antigen on the cancer cell.

If the cell loses CD19, a CD22-directed CAR T-cell product could potentially be used, Brody explains. However, the ultimate goal is to prevent antigen escape rather than treat it with an alternative therapy. 

Additionally, sometimes the cell can lose multiple differentiation antigens in aggregate, says Brody. For example, if a cell loses CD19, CD20, and CD22, dual-specific CAR T-cell therapies will be unable to target the antigen.

Currently, ongoing research is attempting to mitigate antigen escape by targeting the antigen-positive cells that surround the antigen-negative cell, Brody says. This approach could potentiate the bystander-killing effect of the therapy. 

Antigen escape also provides potential rationale to investigate combination therapies with CAR T-cell therapy, bispecific antibodies, and checkpoint inhibitors, concludes Brody. 

Joshua Brody, MD, discusses the challenges of mitigating antigen escape in mantle cell lymphoma.  



Dr. Brody on the Challenges of Antigen Escape in MCL 

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.

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.

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

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai, discusses the development of in situ vaccinations, a vaccine that is created at the tumor site in patients with cancer.

Brody clarifies how cancer vaccines work. The vaccine is used in a therapeutic way rather than to prevent disease. With the vaccine, researchers are teaching a patient’s immune system to recognize cancer.

The in situ approach takes advantage of the fact that the immune system has the tools to stop cancer. The immune system can recognize the cancer at the tumor site where tumor antigens are collected. If they can be mobilized in an immunogenic way, the immune system can in turn recognize the cancer. By using the vaccine at 1 site to induce immune response, T cells will travel throughout the body to kill tumors throughout the body.

2020 International Congress on Hematologic Malignancies

Joshua Brody, MD, discusses the development of in situ vaccinations, a vaccine that is created at the tumor site in patients with cancer.

Joshua Brody, MD

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