Anticancer strategies that work with B-cell malignancies may not work so well with T-cell malignancies. Consider, for example, a strategy that involves wiping out both cancerous and noncancerous B cells. Although this strategy sounds extreme, it needn’t leave patients overly vulnerable to infections. Indeed, most patients can survive without B cells. That isn’t the case with T cells. If a treatment were to wipe out both normal and cancerous T cells, it would leave patients without a functioning immune system and at high risk of dying from infections.
To target T-cell malignancies such as T-cell leukemias and lymphomas, scientists based at Johns Hopkins University have developed an antibody-drug conjugate (ADC). It targets a cell surface protein called T-cell receptor β-chain constant region 1 (TRBC1), and it kills cancerous T cells more zealously than it kills noncancerous T cells. In a study that recently appeared in Nature, in an article titled, “TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers,” the Johns Hopkins team reported that their ADC could “kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models.”
Basically, the ADC combines a TRBC1-targeting antibody and an anticancer drug called SG3249. After latching onto a TRBC1-expressing T cell, the ADC is ingested by the T cell, whereupon SG3249 is released, killing the T cell. Because T-cell cancers express either TRBC1 or TRBC2, whereas normal T cells express a mix of TRBC1 and TRBC2, selective targeting of TRBC1 can potentially eradicate the normal and cancerous T cells expressing TRBC1 while preserving normal T cells expressing TRBC2.
In the Nature article, the Johns Hopkins scientists contrast their ADC approach with an alternative approach, the use of chimeric antigen receptor (CAR) T cell–mediated targeted therapies.
“Preclinical studies showed that targeting TRBC1 can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity, making TRBC1 an attractive target to treat T-cell cancers,” the scientists wrote. “However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells.”
CAR T cells are genetically engineered T cells that are FDA-approved treatment options used in several B-cell cancers. However, in the aforementioned clinical trial, the CAR T cells did not persist inside patients. Such persistence is required if cancer cells are to be killed effectively.
How to explain the lack of CAR T-cell persistence? According to the Johns Hopkins team, which was led by assistant professor of oncology Suman Paul, MBBS, PhD, the CAR T cells targeting TRBC1 are killed by normal T cells.
To get around this problem, Paul and colleagues began developing their ADC approach. They tried two different formulations of ADCs in mouse models of T-cell cancers. After a single injection of one formulation of the treatment, the cancers initially regressed but then recurred. After a single treatment with the anti-TRBC1-SG3249 ADC combination, investigators observed signs of cancer elimination within seven days and the cancers were eventually undetectable, with no recurrences. “The tumors didn’t come back,” Paul said, “and we followed the mice for more than 200 days.”
“Not much drug development has happened in this space of T-cell leukemias and lymphomas,” Paul noted. “Developing treatments for T-cell leukemias and lymphomas is much more difficult than for leukemias and lymphomas arising from immune system B cells.
“We need new therapies for these cancers, but whatever therapies we develop in the space have to be cancer specific. We have to preserve some of the normal T cells and wipe out cancerous T cells at the same time.”
The ADC approach developed by Paul and colleagues was able to eliminate the cancer while preserving half of the remaining normal T cells. “The residual normal T cells should be sufficient to maintain some immune system protection against infectious diseases,” Paul asserted.
“Witnessing the successful elimination of T-cell cancers while sparing normal T cells in preclinical models was truly gratifying,” added Jiaxin Ge, a co-author of the study and a PhD student at the Johns Hopkins Ludwig Center. “We believe this approach has the potential to address a critical unmet need in oncology, and we’re committed to advancing it through further research.”
Tushar Nichakawade, first author on the study and a PhD student at the Ludwig Center, said, “There are so many lessons to learn from the clinic and it has been exciting to be a part of the iterative process of drug discovery. Every therapy has its pros and cons, but the preclinical efficacy of our ADC gives me hope that it can make a difference for patients suffering from these terrible cancers.”
Each year, about 100,000 patients worldwide are affected by T-cell leukemias and lymphomas. Adults with relapsed T-cell cancers have limited therapeutic options and five-year survival rates of 7–38%.
“The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers,” the author of the Nature article concluded. The investigators are now working with an industry partner to conduct early-phase safety and efficacy trials in human patients.
