Immunotherapy Continues on Positive Trajectory in Lymphoid Malignancies

Joshua Brody, MD

The treatment landscape of lymphoid malignancies space is rich with available immunotherapy agents, said Joshua Brody, MD. However, the field continues to push toward improving response rates by refining established modalities, such as CAR T-cell therapy and checkpoint inhibitors, as well as introducing novel modalities.

During the 5th Annual International Congress on Immunotherapies in Cancer^®, a program run by Physicians’ Education Resource^®, Brody, an assistant professor of medicine, hematology, and medical oncology and director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai, gave a presentation on established and upcoming immunotherapies in the lymphoid malignancy pipeline.

“We are somewhat lucky, and maybe a bit spoiled, in lymphoid malignancies, such as lymphomas and some B-cell malignancies, to have [seen] a huge amount of progress [with immunotherapy],” said Brody.

However, lymphoid malignancies are highly heterogeneous. As such, not all patients are able to derive responses from the same therapy, Brody explained.

CAR T-Cell Therapy

CAR T-cell therapy represents a significant advance in the treatment paradigms of several hematologic malignancies, including lymphoid malignancies, said Brody.

“The results [of CAR T-cell therapy treatment] for patients with aggressive B-cell lymphomas have been amazing,” Brody said. “[CAR T-cell therapy] has shown higher response rates [in this space] than any other immunotherapy for any type of cancer; response rates are above 80%. Many of those [responses] are long-lasting, complete remissions [CRs].”

Notably, it is thought that patients who remain in CR for at least 6 to 12 months after CAR T-cell therapy infusion are likely cured of their lymphoma, Brody said. For example, it is likely that around 35% to 40% of patients with diffuse large B-cell lymphoma (DLBCL) who receive CAR T-cell therapy are effectively cured.

“DLBCL is the most common type of lymphoma, and third-line DLBCL [was thought to be] an incurable disease setting,” said Brody. “We [thought we could] cure people in the first- or second-line setting, but not beyond. I’m not sure how we define a miracle, but it seems miraculous to me to change the incurable to partly curable.”

Now ongoing research efforts are attempting to refine CAR T-cell therapies to enhance responses and expand the utility of the modality to other hematologic malignancies beyond DLBCL, acute leukemia, and mantle cell lymphoma, explained Brody. For example, developing armored CAR T cells and fourth-generation CAR T cells—T cells redirected for antigen‐ unrestricted cytokine‐initiated killing—may allow for improved delivery of cytotoxic payloads to liquid as well as solid tumors.

Additionally, novel CAR T-cell therapies may overcome some of the ongoing challenges observed with current, autologous products, such as toxicity, accessibility, and feasibility. For example, utilizing an allogeneic approach to CAR T-cell therapy may allow for an off-the-shelf option that could alleviate the risks of cytokine release syndrome and neurotoxicity.

Bispecific Monoclonal Antibodies

Beyond CAR T-cell therapy, bispecific monoclonal antibodies, such as the investigational CD20/CD3-directed REGN1979 agent, could potentially be used in patients who progress after CAR T-cell therapy. Findings from a phase 1 trial (NCT02290951) demonstrated high objective response rates and CR rates among patients with heavily pretreated, relapsed/refractory non-Hodgkin lymphoma who were treated with REGN1979.¹

Although the toxicity challenges of CAR T-cell therapies will likely not be solved with bispecific antibodies, the novel agents may offer an alternative option that can decrease the risk of adverse effects.

“At least with [bispecific antibodies], we can tweak and optimize [dosing] a bit,” explained Brody. “CAR T-cell therapy is usually a 1-shot therapy, [whereas] bispecifics can be given in low, medium, or high doses. We can up-titrate the therapy to try to minimize or avoid some of these toxicities.”

Additionally, bispecific antibodies are potentially able to avoid antigen escape, which is a common concern with CD19/ CD20-directed CAR T-cell therapies, Brody explained.

Checkpoint Inhibitors

PD-1/PD-L1 inhibitors have transformed treatment in melanoma, lung cancer, renal cell carcinoma, and bladder cancer. However, Hodgkin lymphoma is the most responsive disease to anti–PD-1 agents because chromosomal amplifications or translocations are “hardwired” to overexpress PD-1, Brody said.

As such, responses with checkpoint inhibitors, such as nivolumab (Opdivo), are seen in approximately 70% of patients with Hodgkin lymphoma who progress following autologous stem cell transplant.²

The introduction of checkpoint inhibitors to this space has been particularly encouraging for younger patients who fail curative-intent chemotherapy and who, historically, had dismal prognoses.

Currently, ongoing efforts are attempting to bring PD-1 inhibitors to the second-line and, potentially, up-front settings in combination with chemotherapy.

Vaccines

Although it is true that “hot” tumors are more likely to respond to immunotherapy compared with “cold” tumors, it is not the only factor that contributes to whether a tumor will respond. As such, alternative methods of improving immune response in patients with lymphoid malignancies are being evaluated.

For example, one investigational method is to utilize radiotherapy or other means to mobilize dendritic cells loaded with tumor antigens to antigen-presenting cells. Ultimately, this compound could serve as a therapeutic anticancer vaccine to deliver the antigens, as well as costimulatory signals, to the cancer cells.

An ongoing trial (NCT03789097) led by Brody is currently testing an in situ vaccine combining radiation therapy, the immune cell growth factor Flt3L/ CDX-301, the immune-cell activating factor poly-ICLC, and pembrolizumab (Keytruda).³ Initial findings from the study have yielded encouraging results, according to Brody.

In situ vaccines such as this may be able to cross prime T cells and increase the effectiveness of immunotherapy for patients, Brody concluded.

References

1. Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl 1)762. doi:10.1182/blood-2019-122451
2. Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018;36(14):1428-1439. doi:10.1200/JCO.2017.76.0793
3. Vaccination with flt3L, radiation, and poly-ICLC. Clinicaltrials.gov. Updated July 15, 2020. Accessed December 15, 2020. http://bit.ly/38mQRLl