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.

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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.

Dr. Brody on In Situ Vaccinations for Hematologic Cancers

Joshua Brody, MD, assistant professor, Icahn School of Medicine, director, Lymphoma Immunotherapy Program, Mount Sinai Hospital, discusses exciting new therapies for lymphomas and chronic lymphocytic leukemia (CLL).

In lymphomas and CLL, good therapies exist now, such as B-cell receptor signaling inhibitors like BTK inhibitors and PI3K inhibitors. There are also new agents, such as Bcl-2 inhibitors, that look promising.

Brody hypothesizes that some non-specific immunotherapies will likely show good results in lymphomas and CLL.

Dr. Brody Discusses Exciting Therapies for Lymphomas and CLL

Immunotherapy can induce regressions of even advanced stage cancers, and many of these patients can have prolonged disease remissions. Three broad approaches have moved immunotherapy forward: immunostimulants (eg, 

), which push the gas pedal of the immune system; checkpoint blockade antibodies (eg, 

), which cut the brake lines; and vaccines (eg, 

), which can steer the immune system toward recognizing specific antigens. Unfortunately, the metaphor falls short. If cars had as many gas pedals and brake pedals as the immune system, accidents and gridlock would be endless. The system usually runs itself seamlessly; we have tried clumsily to drive it with halting successes and failures, acknowledging that an owner’s manual would be helpful. Basic immunologists have been writing this manual for the past 40 years and although it’s far from complete, immunotherapists have been reading the early drafts and trying to implement the lessons with some remarkable early success.

A recent example of basic science discovery was the 

, which was awarded for the discovery of dendritic cells (DCs) and the molecular switches that turn them on, the Toll-Like Receptors (TLR). Today, the clinical significance of these basic discoveries has an opportunity to be realized with new clinical grade reagents. Flt3L, a DC growth factor, has completed phase I testing and shown to be safe and effective. Meanwhile, several TLR agonists (eg, poly-IC, imiquimod/resiquimod, CpG) have been shown in a multitude of clinical trials to stimulate activation of distinct subsets of DCs. This progress in basic and applied immunology sits atop our decision tree of possible immunotherapeutic combinations, weighing down the branches, and yielding some low-hanging fruit.

Lymphoma is the fifth most common cancer nationally and one of the few still increasing in frequency. The World Health Organization recognizes more than 60 types of lymphoma, and the most prevalent subtypes fall within the group of low-grade B-cell lymphomas. For these diseases, chemotherapy and antibody therapy induces remissions in most patients, but disease generally recurs and chemotherapy becomes less effective with each successive use. A promising new generation of kinase inhibitors similarly has high response rates but limited durations of response. Ultimately, therapy resistance develops and low-grade lymphomas are incurable with standard therapy. Novel therapies that attack the tumor in a completely different way are needed. If cancer vaccines could become more powerfulwith each successive use—just as we see with booster vaccines in infectious disease&mdash;we could fundamentally change the paradigm of diminishing responses to therapy.

The first generation of vaccines tested in large trials were known as idiotype vaccines, described preclinically in 1987 and clinically in 1992 by Ronald Levy, MD, and colleagues at Stanford. Although this elegant approach frequently induced antitumor antibody responses, the demonstration of antitumor T-cell responses and clinical responses were rare. Ultimately, two large randomized trials showed no clinical benefit with idiotype vaccines.

Recently, we developed a novel approach using the patient’s immune system to recognize and “reject” his or her own lymphoma tumors. This “in situ vaccine” approach consists of low-dose radiotherapy to one tumor site and injection of an immune cell stimulant (a TLR agonist) directly into the same tumor site to activate the small number of immune cells (eg, DCs) there. At the vaccine site, DCs instruct and prime antitumor T cells, which then travel throughout the body to eliminate their tumor targets. We treated 60 patients with the in situ vaccine in trials for low-grade 

 lymphoma and it induced partial and complete remissions, 

. It was equally exciting that—as expected with vaccines&mdash;this therapy actually 

This stark contrast to the paradigm of chemotherapy is encouraging; still, the approach needs to be made even more effective. One likely limitation is that there are very few “professional” antigen-presenting cells, such as DCs, at the tumor site constraining the ability to prime the antitumor T-cell response. Bringing more DCs to the tumor might yield more effective antitumor T cells and a greater number of clinical responses.

Just as red blood cells have erythropoietin and neutrophils have G-CSF, DCs have a predominant growth/differentiation factor known as Flt3L. A recombinant form of the protein recently completed phase I testing in healthy volunteers and was shown to 

drastically increase the number of DCs in peripheral blood

. Preclinical studies in our lab have shown that by injecting this growth factor directly into tumors,the number of intratumoral DCs can be significantly increased (

). Hence the “low-hanging fruit” and rationale behind a newly initiated trial for the in situ vaccine at Mount Sinai School of Medicine.

] will enroll 30 patients with low-grade B cell lymphoma in two cohorts to assess for the recruitment of DCs to the tumor site, the induction of antitumor T cells, and the proportion of patients with systemic clinical responses (ie, occurring outside of the radiotherapy field). The study Principal Investigator, Joshua Brody, MD, is working together with clinical collaborator 

Mount Sinai Human Immune Monitoring Center

The debate over whether the immune system can treat cancer is done. Over the next decade, questions on how best to modulate the immune system to recognize tumors, which tumor antigens are most effectively targeted, and the role of checkpoint blockade, immune stimulants, vaccines, and combinations thereof will predominate as we progress from cancer treatments to cancer cures. For these questions, only enrollment of patients onto clinical trials will provide the answers. The answers, in turn, should provide long and gratifying lives for our patients.

		(1) Intratumoral injections of Flt3L to recruit DC to the tumor site.

		(2) Low-dose radiotherapy (4 Gy) to the tumor to release tumor-associated antigens.

		(3) Intratumoral injections of the TLR agonist poly-IC to activate the tumor-antigen loaded DC.

Articles

Immunotherapy can induce regressions of even advanced stage cancers, and many of these patients can have prolonged disease remissions.

Joshua Brody, MD, of Mount Sinai Hospital

Articles

Dr. Brody on the Role of Immunotherapy in Indolent Lymphomas

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

Dr. Brody on In Situ Vaccinations for Hematologic Cancers

Dr. Brody Discusses Exciting Therapies for Lymphomas and CLL

Novel Vaccine Induces Durable Remissions in Patients With Advanced Lymphoma