T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity.

As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.

Acromegaly presenting with myelopathy due to ossification of posterior longitudinal ligament: a case report.

BACKGROUND: Acromegaly is a rare disease caused by high serum levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), often originating from a pituitary adenoma. Spinal and peripheral joint abnormalities are caused by these hormonal hypersecretions. In particular, the response to GH is involved in the onset of ossification of the spinal ligament in vitro, especially ossification of the posterior longitudinal ligament (OPLL). However, because acromegaly and OPLL are rare diseases, we seldom encounter them in combination. To the best of our knowledge in the English-language literature, this is the first reported case of acromegaly presenting with thoracic myelopathy due to OPLL. CASE PRESENTATION: A 47-year-old woman presented with lower extremity weakness and paresthesia, gait disorder, and bladder disorder without any trauma. The patient's most remarkable symptom was paraplegia, and we diagnosed myelopathy due to cervical and thoracic OPLL. Furthermore, we suspected acromegaly because of the characteristic facial features, and we found a pituitary adenoma by contrast-enhanced MRI. Cervical and thoracic decompression, posterior fixation, and pituitary adenoma resection were performed. CONCLUSION: We report a case of acromegaly that was detected after the diagnosis of OPLL. The main challenge in acromegaly is delayed in diagnosis. Even in this case, the facial features characteristic of acromegaly had appeared at least 9 years ago. Early diagnosis and treatment of acromegaly improve prognosis and reduce exposure to GH and IGF-1 through early intervention and seem to suppress the progression of ligament ossification. Orthopedic surgeons and neurosurgeons need to keep in mind that acromegaly is associated with bone/joint lesions and ossification of the spinal ligament and should aim to diagnose acromegaly early.

Mechanism of action of a T cell-dependent bispecific antibody as a breakthrough immunotherapy against refractory colorectal cancer with an oncogenic mutation.

T cell-dependent bispecific antibody (TDB)-induced T cell activation, which can eliminate tumor cells independent of MHC engagement, is expected to be a novel breakthrough immunotherapy against refractory cancer. However, the mechanism of action of TDBs has not been fully elucidated thus far. We focused on TDB-induced T cell-tumor cell contact as an important initial step in direct T cell-mediated tumor cell killing via transport of cytotoxic cell proteases (e.g., granzymes) with or without immunological synapse formation. Using an anti-EGFR/CD3 TDB, hEx3, we visualized and quantified T cell-tumor cell contact and demonstrated a correlation between the degree of cell contact and TDB efficacy. We also found that cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) secreted by activated T cells, damaged tumor cells in a cell contact-independent manner. Moreover, therapeutic experiences clearly indicated that hEx3, unlike conventional anti-EGFR antibodies, was effective against colorectal cancer (CRC) cells with mutant KRAS, BRAF, or PIK3CA. In a pharmacokinetic analysis, T cells spread gradually in accordance with the hEx3 distribution within tumor tissue. Accordingly, we propose that TDBs should have four action steps: 1st, passive targeting via size-dependent tumor accumulation; 2nd, active targeting via specific binding to tumor cells; 3rd, T cell redirection toward tumor cells; and 4th, TDB-induced cell contact-dependent (direct) or -independent (indirect) tumor cell killing. Finally, our TDB hEx3 may be a promising reagent against refractory CRC with an oncogenic mutation associated with a poor prognosis.

Percutaneous fixation of avulsion fracture at the plantar lateral base of the first metatarsal using ZipTight Fixation System: A case report.

Isolated avulsion fracture of the peroneus longus tendon insertion at the base of the first metatarsal without injury of the tarsometatarsal joint is very rare. Similar to most avulsion fractures, this type of injury is caused by strong tension exerted by the peroneus longus tendon. The mechanism leading to this lesion and treatment options are not clearly defined. Several surgical techniques have been advocated for this fracture, including excision of an avulsion fragment and open reduction for internal fixation through the medial aspect of the foot or minimal plantar incision. We have described a method of percutaneous fixing of the avulsion fracture at the plantar lateral base of the first metatarsal using the ZipTight Fixation System (Zimmer Biomet Warsaw, Indiana, USA), which offers the advantage of allowing a rigid fixation and minimal invasive surgical technique for a small fragment.