Chimeric antigen receptor (CAR) T-cell therapies are a major advance in the treatment of hematologic malignancies and are making inroads in solid tumors, but there is room for improvement in their design, since not all patients respond, and those who do may relapse. Researchers are studying multiple avenues for fine-tuning these therapies to make them more effective and less toxic. At the recent American Association for Cancer Research (AACR) Virtual Meeting: Advances in Malignant Lymphoma, investigators discussed promising strategies for the future.^1-3

“We have a Model T Ford, but we need a Mustang,” said session moderator Renier J. Brentjens, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York. “CAR T-cell therapies are in their infancy. They have undergone significant evolution since their first introduction, and they will continue to evolve.”

“CAR T-cell therapies are in their infancy. They have undergone significant evolution since their first introduction, and they will continue to evolve.”

— Renier J. Brentjens, MD, PhD

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The first-generation CAR T cells were directed to the CD19 antigen. Since then, second-generation CAR T cells were designed with two signaling domains, including CD18 and 41bb. Third-generation CAR T cells have three signaling domains.

“The most experience and the most success has been with CD19 CAR T cells,” Dr. Brentjens said.

Nevertheless, he continued, “Trials have shown that while patients do achieve complete responses and have durable responses, patients who have partial responses tend to do much worse and responses tend not to be durable, so there is still significant room for improvement to optimize treatment for these patients.”

‘Armored’ CARs

Dr. Brentjens described approaches with fourth-generation CARs, which are designed to secrete costimulatory ligands, such as interleukin (IL)-18, CD40, PD-1–blocking scFv, and IL-36. Preliminary studies are being done on these strategies, and clinical trials exploring at least one of these approaches are expected to start up in 6 to 12 months.

“A CAR T cell can find the tumor and act as a ‘micropharmacy,’ delivering proinflammatory agents such as cytokines, which can unleash the patient’s own immune system. We call this ‘armored CAR T.’ We engineer the cells to persist long enough to eradicate the tumor. Armored CAR T cells can deliver cytokines, antibodies, and ligands to reeducate patients’ endogenous immune system,” he explained. “We are excited about this approach,” he added.

Studies in mice have shown that IL-18–secreting CAR T cells have improved long-term survival and recruited an endogenous antitumor response. Another example of an armored CAR T cell is one that secretes CD40, which is activated on T cells and targets the tumor, inducing senescence or apoptosis. CD40 ligand–modified CAR T cells targeted to CD19 have induced long-term survival in tumor-bearing mice.

CAR T cells secreting PD-1–blocking scFv (recombinant anti-CD25 immunotoxin RFT5) have increased antitumor function and may be useful in solid tumors as well, Dr. Brentjens suggested.

Dr. Brentjens’ lab has been focused on developing IL-36–gamma secreting CAR T cells. “A variety of preclinical studies show that IL-36–gamma induces activation of the endogenous immune system and suppresses tumor growth in mice. Dr. Carol Li and colleagues in our lab constructed and validated an IL-36–secreting CAR T cell. In vivo studies in pretreated mice suggest that this approach can significantly enhance survival and tumor control and has the potential to avoid antigen escape,” Dr. Brentjens said.

CD5 and CD7 for T-Cell Lymphoma

“There are not many treatment options for patients with relapsed or refractory T-cell lymphomas. They are difficult to target with CAR T-cell therapy,” explained Maksim Mamonkin, PhD, of Baylor College of Medicine, Houston.

CD5 is a surface receptor in T cells and some B cells and is widely expressed in T-cell lymphoma. Second-generation CARs targeting CD5 are being studied. Expression of a CD5 CAR results in a rapid and complete loss of accessible CD5 in T cells, so the CAR T cells can overcome fratricide (ie, self-targeting).

“We were able to clear quite bulky disseminated disease in three of six patients with T-cell lymphoma [with CD5 CAR T-cell therapy].”

— Maksim Mamonkin, PhD

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The first-in-human study of CD5 CAR T-cell therapy showed that three out of six patients with T-cell lymphoma enrolled on the first two dose levels ultimately achieved complete remission. Results were not as promising in five patients with lymphoblastic disease, he added, where only one transient complete response was observed. CD5 CAR T-cell therapy was given as a single dose as a bridge to transplant to all patients except one, who received a second infusion after demonstrating initial response. “This is unpublished work,” Dr. -Mamonkin noted.

“We found expansion and persistence of CD5 CAR T cells in peripheral blood. Expansion in most patients peaks by week 2, and we can detect the cells out to 9 months in some patients. We were able to clear quite bulky disseminated disease in three of six T-cell lymphoma patients,” Dr. Mamonkin said. “Remarkably, CD5 CAR T cells do not induce complete ablation of endogenous CD5-positive T cells, and we do not observe T-cell aplasia even in patients with complete tumor regression. We are continuing to escalate CD5 CAR T-cell dose and making manufacturing adjustments to further increase their potency.”

CD7 CAR T cells are also under study in the United States and China, where researchers are using genome editing to minimize CD7 gene expression and overcome the problem of T-cell fratricide. “We have previously reported the activity of CD7 gene-edited CD7 CAR T cells in preclinical models of T-cell malignancies and now are gearing up to evaluate this approach in patients with T-cell lymphoma,” Dr Mamonkin said.

“Fratricide is an inherent problem when you try to use T cells as therapy in the presence of normal T cells. Dr. Mamonkin showed that CD5 and CD7 can be targeted and may minimize that fratricide aspect. For reasons that are not clear, the normal T cells can be targeted, and patients retain their normal T-cell population when going after CD5,” Dr. Brentjens said.

“CD5 CAR T cells are already in early clinical trials. T-cell cancers are not that common. We need to translate this approach to more common cancers so more patients can benefit,” he added. “This work is important because T-cell malignancies are extremely hard to treat, and there have been few advances for this malignancy in a long time. This offers hope for a curative therapy and is a significant step forward,” Dr. Brentjens commented.

Factors Determining Efficacy and Toxicity

“There is increasing evidence that host, tumor, and CAR T-cell factors are associated with the efficacy and toxicity of CAR T-cell therapy,” stated Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center, Houston.

Dr. Neelapu reviewed all the data from various studies with different designs to give an overview of what is known to date about these factors. Host factors that are associated with toxicity and efficacy include age, performance status, comorbidities, inflammatory state, type of conditioning, immune cell fitness, prior therapies, and the microbiome.

Sattva S. Neelapu, MD

“One of the most important factors is the overall functional status of the patient. A worse performance status is associated with a worse outcome,” he said. “Baseline inflammatory status is also associated with outcomes. A higher inflammatory state is associated with worse toxicity.”

Cytarabine/fludarabine conditioning is associated with higher complete response rates compared with cytarabine/etoposide, according to Dr. Neelapu.

Tumor and CAR T-Cell Factors

Tumor burden is associated with outcome in multiple studies. “Higher tumor burden was associated with lower complete response rates and also with higher toxicity rates,” Dr. Neelapu noted.

Antigen density and antigen loss are also associated with efficacy and toxicity, as are tumor subtype and the microenvironment. Loss of CD19 is associated with resistance to CAR T-cell therapy. Other associated factors are CD8 T-cell density and the tumor microenvironment.

The CAR T-cell product factors associated with toxicity and efficacy include the dose, the binder (ie, scFv), the costimulatory molecules, signaling domains, the hinge transmembrane, phenotype, polyfunctionality, and composition.

“There is increasing recognition that CD28 CARs may be associated with greater neurotoxicity and higher cytokine production,” Dr. Neelapu said. “CAR T cells with higher polyfunctionality are associated with better response,” he added.

Final Comments on the Session

“[Dr. Neelapu’s presentation] was an outstanding overview. [He] had to look at different data comparing apples to oranges among a number of trials, none of which had the same protocol. He teased out what is important in improving efficacy and minimizing toxicity. This will become an even bigger issue for next-generation CAR T cells—to deliver therapy safely without causing too much toxicity,” Dr. Brentjens commented.

Weighing in on all of the new approaches discussed in this session, Dr. Brentjens said: “We want to make these cells more potent in B-cell malignancies and also translate them to other cancers including solid tumors. The technology [for CAR T cells] is in its infancy, and the ceiling is quite high. I’m an optimist.”

He continued: “We have shown in numerous incidences that T cells are able to target and kill tumor cells. Now what we need to do is translate that fact to the clinical setting, to use these cells optimally to eradicate cancer. It is conceivable in the future that cell therapies will be able to replace chemotherapy, which causes so much toxicity,” Dr. Brentjens said. 

DISCLOSURE: Dr. Brentjens has received royalties from June Therapeutics/BMS, research funding from Juno Therapeutics, and consultant fees from Gracell Biotechnology. Dr. Mamonkin disclosed financial relationships with Xenetic Biosciences and has received licensing/royalty fees from Fate Therapeutics. Dr. Neelapu has received research support from Kite/Gilead, Merck, BMS, Cellectis, Poseida, Karus, Acerta, Allogene, Unum Therapeutics, and Precision Biosciences; has served as a consultant or advisor for Medscape, Aptitude Health, BioAscend, and MJH Life Sciences; has received royalties from Takeda Pharmaceuticals; and holds patents related to cell therapy.

REFERENCES

1. Brentjens RJ: CARs and armored CARs: Improving CAR T-cell therapy for cancer. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Presented August 18, 2020.

2. Mamonkin M: CAR T cells for T-cell lymphoma. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Presented August 18, 2020.

3. Neelapu SS: Determinants of CAR-T outcomes: Host, tumor, and product. 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma. Presented August 18, 2020.