Clin Cancer Res
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Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells. ⋯ A combinatorial costimulatory design allows the use of very low-affinity binding domains (K d < 1 μmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.
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Despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. T-cell-redirected lysis triggered by bispecific antibodies recruiting T cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and CD38 is a tumor-associated antigen with near-universal expression in multiple myeloma. Thus, an anti-CD38/CD3 bispecific T-cell-recruiting antibody has the potential to be an effective new therapeutic for multiple myeloma. ⋯ These findings support the clinical development of AMG 424, an affinity-optimized T-cell-recruiting antibody with the potential to elicit significant clinical activity in patients with multiple myeloma.
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Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients. ⋯ This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.
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The FDA approved pembrolizumab on May 23, 2017, for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H), or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and for the treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The FDA granted the approval based on an understanding of the biology of MSI-H/dMMR across different tumors along with the clinically important effects on overall response rate (ORR) observed in patients who were enrolled in 1 of 5 single-arm clinical trials. ⋯ Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed across prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on a common biomarker rather than the primary site of origin.
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Over the last several years, several molecular aberrations have been unevenly described across cancers, although the distinct functional relevance in each biological context is not yet fully understood. Novel discoveries have led to the development of drugs tailored to the molecular profile of patients, thus increasing the likelihood of response among biomarker-selected patients. In this context, there has been a progressive redefinition of a precision medicine framework where evidence-based development and earlier approvals might now be driven by this molecular information. ⋯ Food and Drug Administration in an histology-agnostic manner. Because we anticipate that agnostic-histology approvals will continue to grow, we aim to provide insight into the current panorama of targeted drugs that are following this strategy and some premises to take into consideration. Clinicians and regulators should be prepared to overcome the associated potential hurdles, ensuring that uncertainties are dealt with properly and allowing new, promising agents to arrive faster to the market.