A major aim of cellular immunotherapy is to efficiently activate and direct T cells against cancer cells while leaving healthy cells untouched. This is a potent approach to targeting and optimizing treatment by harnessing a patient’s own immune system to fight against cancer. In recent years, two different approaches have been undertaken to direct T cells against tumors. The first, CAR-T, involves the genetic modification of T cells with chimeric antigen receptors (CARs) to seek out and kill tumor cells expressing target antigens. The second, T-cell engagers (TCEs), uses antibodies designed to simultaneously bind two targets with the goal of bringing T cells and targeted tumor cells together to prime the immune cells against that tumor. Both approaches have seen notable successes in blood cell cancers but may have limited efficacy against solid tumors. Both also have advantages and disadvantages that may impact their suitability in different therapeutic settings.
CAR-T
Currently approved CAR-T treatments, Gilead’s Yescarta and Novartis’ Kymriah, both of which target the CD19 receptor, have shown high response rates in B-cell malignancies, including non-Hodgkin’s lymphoma (NHL, over 50% complete response); chronic lymphocytic leukemia (CLL, 70% overall response rate); and acute lymphoblastic leukemia (ALL, 90% ORR), although patients frequently relapse. Both treatments are autologous therapies that require T cells to be harvested from the patient, engineered and expanded in the laboratory — a process that takes three to four weeks. The considerable wait time between T-cell harvest and treatment makes CAR-T therapy challenging for patients with rapidly advancing disease. CAR-Ts are also associated with significant risk of serious adverse events, particularly neurotoxicities and potentially life-threatening cytokine-release syndrome (CRS), or “cytokine storm.” Thus, administration of CAR-T therapies is currently limited to specialized centers with medical personnel who are highly trained in the procedure and the management of the therapy’s risks.
To increase safety, several strategies to fine-tune the activity and timing of CAR-T are being explored. These include engineering CAR-Ts with ON-OFF switches that allow the cells’ anti-tumor activities to be controlled via administration of an antibody or a small molecule drug, or via withdrawal of an activating molecule co-administered with the CAR-T therapy.
Efforts are also underway to enhance the applicability of CAR-T therapies. “Off-the-shelf” allogeneic CAR-T treatments are being developed which could eliminate the wait time and expense for ex vivo T-cell processing. In patients who respond to treatment, the reduction in disease burden is significant, often leading to undetectable levels that could allow for a less-intensive conditioning treatment prior to stem cell transplantation. In addition, a single CAR-T infusion remains active in the patient for an extended period, and this persistent activity is critical to the treatment’s success as a one-time, stand-alone therapy.
Initial CAR-T treatments have mostly targeted CD19, but this may lead to a down-regulation of the antigen and, ultimately, treatment failure. To overcome that limitation, researchers are exploring additional antigen targets. In a Phase 1 dose escalation trial in patients with NHL or CLL, a bi-specific CAR-T targeting both CD19 and CD20 demonstrated an 82% complete response rate, with all of the patients receiving the highest dose responding to the therapy.
Additionally, at the end of March, the FDA approved Bristol Myer Squibb/bluebird bio’s Abecema (ide-cel), which targets the B Cell Maturation Antigen (BCMA), as the first CAR-T treatment for multiple myeloma. Approval was based on data from the ongoing pivotal KarMMa trial, which has reported an ORR of 72% and CR of 28%, with 65% of responders remaining in remission for at least 12 months. Other CAR-T treatments targeting CD38 (B cell acute lymphocytic leukemia) and CD138 (multiple myeloma) are also under investigation.
T-cell Engagers
The first commercially available TCE, Amgen’s BLINCYTO, which binds CD19 on B cells and CD3 on T cells, was approved in December 2014 for the treatment of relapsed or refractory B-cell ALL. Since then, dozens of anti-cancer TCEs have entered clinical trials as potential treatments for lymphoma and other hematologic malignancies. Most, however, are still in the early stages of clinical testing.
For example, Genentech’s mosunetuzumab, a CD20/CD3-targeting TCE that received Breakthrough Therapy designation from the FDA in 2020, has shown promise in an initial Phase 1/2 clinical trial. Among 124 evaluable patients with aggressive lymphoma, the TCE demonstrated an ORR of 37%, with 19% of those patients achieving CRs. The ORR increased to 63% and CCR to 43% in 67 patients with indolent lymphoma. Moreover, in 18 patients who had previous failed CAR-T, the ORR was 39%, with a 23% CR. In this case, researchers hypothesized that mosunetuzumab may help re-engage persistent CAR-T cells and boost the effect of the patient’s prior treatment. Regeneron’s odronextamab (REGN1979), another CD20/CD3 TCE, is showing similarly promising results in a variety of lymphomas. However, in December 2020, the FDA placed a partial clinical hold on its study, due to a higher-than-expected incidence of Grade 3 CRS; the company hopes to resume enrolling patients soon .
While CRS and neurotoxicities remain a safety concern for TCE therapies, the ability to adjust the dosing of these therapies makes it easier to control adverse reactions, as well as enable repeat dosing over time. Moreover, while most TCEs require administration by continuous infusion, Genentech is developing the first subcutaneous TCE, GEN3013. In preclinical and initial Phase 1 testing, this CD3/CD20 TCE has shown high potency at low doses against several forms of lymphoma, and its slow absorption from the injection site helped to mitigate risks of adverse events.
Not only are TCEs off-the-shelf treatments, but they are manufactured via standard recombinant production methods that allow for lower cost and greater patient access to therapy. TCEs exploit the patient’s existing large pool of antigen-experienced T cells, thus quickly expanding the group of cells able to respond against a tumor.
The smaller size of TCEs enables greater tissue penetration, suggesting potential usefulness against solid tumors. Developing a new generation of TCEs for solid tumors has become a very active area of research investment, with Amunix Pharmaceuticals and Janux Therapeutics raising $117M and $56M venture financings respectively since the start of 2021. Moreover, in early March, Takeda exercised its option to buy Maverick Therapeutics and its proprietary TCE-engineering platform for solid tumors for up to $525 million. Maverick’s TAK-186 TCE, which targets EGFR-expressing tumors, recently entered Phase 1/2 testing. A second TCE, TAK280, is slated to begin clinical trials in the second half of this year against B7H3-expressing tumors. Unlike previous TCEs that are systemically active upon administration, Maverick’s treatments exploit the tumor microenvironment to trigger their cancer-killing activity only at the tumor site.
It is likely that both CAR-Ts and TCEs will have an important role in cancer therapy, given their relative advantages, especially if off-the shelf CAR-T therapeutics are successfully introduced. The key to the success of both approaches will be increasing the therapeutic window by significantly decreasing CRS-related and neurologic toxicities while maintaining or increasing treatment efficacy.