CAR T cell therapy

Enhanced T Cell Therapy Found Effective against Multiple Solid Tumors

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Results of the first-in-human trial of an enhanced T cell therapy that targets multiple solid tumors bearing the antigen MAGE-A4, showed noteworthy outcomes in several cancers, particularly synovial sarcoma. The multi-center phase I clinical trial (clinical trial ID: NCT03132922) was led by researchers at the University of Texas MD Anderson Cancer Center and sponsored by Adaptimmune, a clinical-stage biopharmaceutical company focused on developing cancer immunotherapies.

The findings were published in the journal Nature Medicine on January 9, 2023 “Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial.”

The enhanced T cell therapy, afamitresgene autoleucel (afami-cel) achieved an objective response rate (ORR) of 44% in patients with synovial sarcoma while the overall response rate across all types of cancers tested in this trial was 24%. (ORR, defined as the proportion of patients with a complete or partial response to treatment is a common endpoint in cancer drug trials.) These early proof-of-concept findings establish acceptable safety of the treatment regimen and support the use of this novel cell therapy for solid tumors.

David Hong, MD, professor of investigational cancer therapeutics, and principal investigator of the study said, “These high response rates are significant because patients with synovial sarcoma really have very few options after high-dose chemotherapy with ifosfamide.”

MAGE-A4 (Melanoma-associated antigen A4) is a protein expressed in solid tumors such as synovial sarcoma (SS), myxoid/round cell liposarcoma (MRCLS), non-small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and ovarian, urothelial, melanoma and gastroesophageal cancers. Its expression in healthy tissue is limited to immune-privileged locations. MAGE-A4 is processed within the cell and fragments of it are flagged on cell surfaces together with human leukocyte antigens (HLAs). The combination of MAGE-A4 and HLAs forms a recognizable epitope for natural low-affinity T cell receptors (TCRs).

Immune checkpoint blockade has good clinical activity in some patients with some solid tumors that express MAGE-A4 such as melanoma, but the response may not be as good in other types of solid tumors such as synovial sarcoma.

Unlike chimeric antigen receptor (CAR)-based cell therapies that detect cell surface proteins, TCR therapies, including afami-cel, can detect proteins found within cells and more accurately target solid tumor cells without the toxicity to healthy cells often occurs with CAR therapies.

Afami-cel is an autologous and enhanced T cell therapy where a specific, high-affinity TCR against a fragment of MAGE-A4 (residues 2030 to 239) presented by HLA-A*02 is transduced through a lentiviral vector.

Earlier preclinical studies have shown that that this enhanced TCR responds strongly upon encountering MAGE-A4 peptide fragments that are presented on several common HLA-A2 alleles, inducing potent cytotoxic effects and effector cytokine release against multiple types of cancers that express MAGE-A4.

As part of the phase I trial, 38 patients with an average of three prior lines of therapy, were treated with afami-cel. Participants were 92% white and 58% male. Sixteen patients had synovial sarcoma, nine patients had ovarian cancer, three had head and neck cancer, two each had esophageal, non-small cell lung, myxoid/round cell liposarcoma and urothelial cancer, and one each had gastric cancer and melanoma.

All patients experienced some treatment-related adverse events, including low blood cell counts (lymphopenia, leukopenia, neutropenia, anemia and thrombocytopenia) and two patients had trial-related deaths. This led to the researchers lowering the maximum age at screening and discontinuing the high-dose cyclophosphamide lymphodepletion.

“The overall toxicity from afami-cel was manageable, and we saw evidence of early activity in [several] cancer types,” said Hong.  “These results suggest this is an approach with the potential to work in solid tumors where there are currently no approved cellular therapies.”

These optimistic results has spurred a phase II trial of afami-cel (NCT04044768) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.

CAR T-Cell Therapy Shows Durable Activity in Heavily Pretreated Multiple Myeloma

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B-cell maturation antigen most promising myeloma target for CAR T-cell therapy

Immunotherapies are becoming the next-generation therapies for multiple myeloma.

The immune microenvironment is immunosuppressive, which makes this disease susceptible to cellular therapy with chimeric antigen receptor (CAR) T-cell therapy. CD-19 targeted CAR T-cell therapy has shown activity in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The most promising target in multiple myeloma is B-cell maturation antigen (BCMA).

“BCMA is a good target because it is expressed on normal and malignant plasma cells and promotes multiple myeloma cell survival,” said Adam D. Cohen, MD, director of myeloma immunotherapy at the University of Pennsylvania Abramson Cancer Center in Philadelphia.

In a presentation at the American Society of Hematology annual meeting, he explained that BCMA-targeted therapies, including CAR T cells, show preclinical and early clinical activity in myeloma. The BCMA CAR T-cell trial he reported divided multiple myeloma patients into three cohorts, including CAR alone with no lymphodepletion, with cyclophosphamide first, and with lower and higher doses of CAR cells. The patients had a median of seven prior lines of therapy, and almost all (95%) had high-risk genetics.

At the time of the analysis, 24 patients, mean age of 58, had been treated (nine in cohort 1, five in cohort 2, and 10 in cohort 3). All have successfully manufactured at least minimum target dose.

A total of 11 of 24 patients (46%) achieved an objective response, and median duration of response is 4 months. Two patients had a complete response (CR) — one in cohort 1 for 24 months, and one in cohort 3 for 6 months.

Toxicities remain cytokine release syndrome (CRS) in six patients and neurotoxicity in six, but there was no increased toxicity with cyclophosphamide, Cohen reported.

“CAR T-BCMA has activity in heavily pretreated multiple myeloma. Lymphodepletion is not required for robust expansion and response. Cyclophosphamide may increase the frequency of patients with strong expansion.”

Two other multicenter trials of CAR T-cell therapy in multiple myeloma also show durable responses, with some approaching 1 year, he noted.

At the 2017 American Society of Clinical Oncology annual meeting, Chinese researchers presented the results of treatment with a novel, proprietary CAR T-cell product, LCAR-B38M, targeting BCMA. All 19 patients with relapsed/refractory multiple myeloma responded, and 14 of 19 (74%) followed for a median of 4 months achieved a stringent CR and have not recurred. The majority (14 patients) experienced mild or manageable CRS, and five patients were even free of diagnosable CRS.

In another presentation at ASH17, durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma were reported with bb2121 anti-BCMA CAR T-cell therapy.

BB2121 is a second-generation CAR construct targeting BCMA, consisting of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB co-stimulatory motif to promote proliferation and persistence, and a CD3-zeta T cell activation domain.

The phase I study, conducted at nine sites in the United States, is the first U.S.-based multicenter study of a CAR T-cell therapy engineered to target BCMA. The study included 21 evaluable patients, median age of 58, who were enrolled in the dose-escalation phase. All had relapsed/refractory disease after a median of seven prior treatments, including a stem cell transplant. The patients had received three or more prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory, and had at least 50% BCMA expression on malignant cells.

A one-time infusion of this investigational CAR T-cell therapy elicited an 86% overall response rate. Among 18 patients who received higher, active doses of infused CAR T cells, the response rate increased to 94%, with manageable adverse effects, reported researchers led by James Kochenderfer, MD, of the National Cancer Institute’s Center for Cancer Research.

Among these 18 patients, 10 (56%) had a CR, and nine of 10 evaluated for minimal residual disease (MRD) using sensitive genetic tests achieved an MRD-negative response. After a median follow-up of 40 weeks, the median progression-free survival had not been reached; four patients have progressed.

The duration of ongoing response is more than 1 year with no additional myeloma therapy, the researchers reported, noting that responses deepened over time — PFS at 6 months was 81% and at 9 months, 71% — and responses continued to improve as late as month 15, from a very good partial response to CR.

The CAR T-cell therapy was generally well-tolerated, and no dose-limiting toxicities were observed in dose escalation, the team noted. Cytopenias were mostly related to cyclophosphamide/fludarabine lymphodepletion. Patients recovered to less than Grade 3 cytopenias by month 2.

Five patients died, three due to disease progression. Two patients were being treated at active doses in CR at the time of death. Fourteen patients had one or more serious adverse events. Four patients had CRS grade 1-2 that required hospitalization, and two patients developed pyrexia.

Kochenderfer et al said they believe that specific targeting with this CAR T-cell therapy is safe and a logical way to attack multiple myeloma.

Cohen summed up: “BCMA is the most promising target for immunotherapy in multiple myeloma. CAR T-cell therapy leads to high response rates. We are in the early days for CAR T-cell therapy for multiple myeloma, but the future is bright.”

Still, he added, many questions and challenges remain, including determining optimal patient populations, how to manage toxicities, and assessing sequencing or combining immunotherapies with current therapies.

“Fine Tuning” Engineered T Cells May Extend Immunotherapy Approach to More Cancer Types

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A T cell bound to multiple beads

An engineered CAR T cell (center) binding to beads, which cause the T cell to divide. In CAR T cell therapy, the engineered T cells are expanded into the hundreds of millions and then infused back into the patient.

Engineering immune cells to have a decreased ability to bind to their targets on cancer cells doesn’t appear to impair their ability to kill cancer cells, but it may cause them to spare healthy cells that have low levels of the same molecular target.

The findings, which come from two new studies performed in cancer cell lines and mice, suggest a way to make an investigational form of immunotherapy, known as CAR T cell therapy, a potential treatment option for more cancers, say the investigators who led the studies.

Results from both studies were published September 1 in Cancer Research.

Overcoming ‘On-Target, Off-Tissue’ Toxicity

To date, CAR T cell therapy has been tested primarily in blood cancers, demonstrating remarkable results in some patients, including complete remissions that have lasted for many years in patients with advanced disease.

Producing this therapy is a highly complex process that involves engineering T cells collected from patients’ blood to produce special receptors on their surfaces — called chimeric antigen receptors, or CARs. The CARs are designed to bind to specific molecules, or antigens, that are found at higher than normal levels (overexpressed) on the surface of cancer cells. The engineered T cells are then grown in the laboratory into hundreds of millions of cells and infused back into the patient.

A substantial obstacle to extending the study of CAR T cells to patients with solid tumors has been “on-target, off-tissue toxicity,” where the engineered T cells “don’t discriminate between cancer cells and normal cells,” explained Daniel W. Lee, M.D., of NCI’s Center for Cancer Research, who is leading clinical trials of CAR T cells in children with cancer.

This phenomenon is a result of the difficulty in finding suitable target antigens on cancer cells in solid tumors that aren’t also found on normal cells, which makes them susceptible to attack by the T cells, a direct cause of side effects.

Affinity Tuning to the Rescue?

By decreasing the affinity of the engineered T cells for their target antigens, this new approach may offer a way to overcome this barrier, authors from both studies suggested.

In the first study, a research team led by Yangbing Zhao, M.D., Ph.D., of the University of Pennsylvania, tested CAR T cells engineered to target the HER2 protein (also called ErbB2), which is overexpressed in approximately one-fourth of breast cancers, as well as in several other solid tumors.

Dr. Zhao and his colleagues manufactured a series of CAR T cells that had either a strong attraction (high affinity) or a low attraction (low affinity) to HER2. Studies in cell lines and mice showed that the affinity of the CAR T cells for HER2 affected their ability to distinguish between low- and high-HER2 expressing cells.

For example, in mice bearing HER2 overexpressing tumors on one side of their body and low HER2 expressing tumors on the other side, inoculating them with the high-affinity CAR T cells shrunk tumors on both sides. But when the mice were inoculated with the low-affinity CAR T cells, only the high HER2-expressing tumors regressed, while the low-expressing tumors continued to grow.

The second study, led by Laurence Cooper, M.D., Ph.D., of Ziopharm Oncology Inc., formerly of The University of Texas MD Anderson Cancer Center, and his colleagues, reported similar findings in a different experimental model. The research team constructed CAR T cells that had either high or low affinity for EGFR, a tumor-associated antigen that is overexpressed in more than 60 percent of human glioblastoma tumors, among other cancers, but in low levels on normal cells.

In an animal model of glioblastoma that overexpresses EGFR, both the high- and low-affinity CAR T cells shrank the tumors. But, because of their toxicity, overall, the high-affinity T cells did not substantially improve how long mice lived compared with untreated mice. Survival was improved, however, in mice treated with the low-affinity CAR T cells. In mice with low EGFR expressing tumors (a stand-in for normal cells with low EGFR expression), the high-affinity CAR T cells shrank tumors and appreciably improved how long some mice lived, whereas the low-affinity CAR T cells had little effect on tumors or survival.

Much of the research to improve CAR T cell performance has been focused on enhancing the activation of T cells by modifying the portion of the engineered receptor that is inside the cell, Dr. Cooper explained in a news release.

“Our study has shown that another possibility is to tweak the extracellular portion of the CAR that docks with the tumor by adjusting its affinity for the target protein,” he said.

Still Work To Do

More research is needed to determine whether low-affinity CAR T cells are a viable option for solid tumors, Dr. Lee cautioned.

The mouse models used in these studies, for example, are very limited in their ability to predict side effects from low-affinity CAR T cells, he continued.

“And, theoretically, the price one pays for an affinity-tuned CAR is a lower response rate or the depth of response—a partial response versus complete response,” Dr. Lee said. “We just won’t know this until these CARs enter clinical trials.”

Affinity-tuned CAR T cells are just one option being studied for extending this treatment approach to patients with solid tumors, he added. “The field is actively trying to overcome this limitation.”