BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control.

BACKGROUND: Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses. METHODS: Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed. RESULTS: FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39-CD69- stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors. CONCLUSIONS: These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates.

Postoperative Restrictive Opioid Protocols and Durable Changes in Opioid Prescribing and Chronic Opioid Use.

Importance: Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients. Objective: To investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use. Design, Setting, and Participants: In this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019. Main Outcomes and Measures: Main outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured. Results: A total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P < .001). The ROPP implementation led to a 45% decrease in prescribed opioids after surgery (mean [SD], 157.22 [338.06] mean morphine milligram equivalents [MME] before ROPP vs 83.54 [395.70] MME after ROPP; P < .001). Patients in the post-ROPP cohort requested fewer refills (367 of 2051 [17.9%] vs 422 of 2017 [20.9%] in the pre-ROPP cohort; P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P < .001) and those without cancer (6.1% [19 of 310] to 2.7% [16 of 600]; P = .02). Conclusions and Relevance: In this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

Implementing an Integrative Survivorship Program at a Comprehensive Cancer Center: A Multimodal Approach to Life After Cancer.

BACKGROUND: This article describes the development of an integrative survivorship program at an urban National Cancer Institute-designated comprehensive cancer center with three closely linked components: a Survivorship Clinic with dedicated staff, a network of Support Services including Wellness, and an Integrative Medicine Program. DEVELOPMENT: We first defined the parameters of survivorship care and developed a patient-centric model that determined the optimal timeframes for transitioning these patients from the oncology clinic to a centralized survivorship clinic. Survivorship care includes the development of a survivorship care plan (SCP) for each patient at their initial visit to the program. Quality-of-life assessments are used in real time to guide clinical decision making to referrals to supportive care services, including educational events, expert consultations, and treatment using integrative and complementary therapies, access to legal services, community resource information, and support group activities for cancer survivors and caregivers. Integrative therapies were added to support the needs of this new program, including recruiting a nutritionist and acupuncturist, and developing a yoga, mindfulness, and Reiki program. Population served: As of June 2018, 908 people have accessed our survivorship clinic, receiving a complete clinical assessment and SCP. Patients are routinely referred to support services based on the individual needs and ongoing symptoms from treatment. The majority of referrals are made to acupuncture, Healing Touch or Reiki, nutrition, psychosocial oncology, and yoga. CONCLUSIONS: Developing a successful integrative survivorship program requires some essential features, including institutional support, strong leadership, a clear vision of how the clinical program will function, a dedicated team that is willing to do what it takes to get the program off the ground, and clinical oncology champions to refer patients into the program. With the development of this program, this multimodal approach to patient-centric care is maintained throughout the spectrum of care, from diagnosis to survivorship.

Platinum-acridinylthiourea conjugates show cell line-specific cytotoxic enhancement in H460 lung carcinoma cells compared to cisplatin.

Recently, we reported a new class of DNA-targeted hybrid platinum-acridine agents. The parent intercalator, ACRAMTU, a 9-aminoacridine derivative, intercalates into the minor groove of DNA, causing the corresponding prototypical conjugate, PT-ACRAMTU (type I/n=2), to form DNA adducts dissimilar to traditional platinum drugs. Both these agents show cytotoxic activity in leukemic and ovarian cancer cells. Following the use of clonogenic survival assays, we report on the cytotoxic effects of ACRAMTU, PT-ACRAMTU, and three PT-ACRAMTU derivatives, on additional cell lines including colon (RKO), lung (H460), and cisplatin-sensitive (A2780) and cisplatin-resistant (A2780/CP) ovarian cells. While a dose-dependent effect was observed with both ACRAMTU and PT-ACRAMTU, an enhanced cytotoxic effect was seen with PT-ACRAMTU in all cell lines. PT-ACRAMTU appeared to have a similar IC50 value to cisplatin except in H460 lung cancer cells in which PT-ACRAMTU had a twofold lower IC50 value. PT-ACRAMTU appeared to act in a time-dependent manner. In H460 cells the IC50 value of PT-ACRAMTU was 235-fold higher following a 1-h incubation than following a 24-h incubation (0.27 microM), while following an 8-h incubation the IC50 value was 0.41 microM. Three derivatives of PT-ACRAMTU were also tested. A tetraalkylated derivative, type II/n=2, generated the highest IC50 values in all cell lines, while the trialkylated derivative, type III/n=2, generated IC50 values similar to its isomer, PT-ACRAMTU. PT-ACRAMTU with an added CH2 group in the thiourea linker (type I/n=3) showed IC50 values similar to the type I/n=2 prototype in H460 lung cells. An apoptotic response to PT-ACRAMTU appeared to be generated in H460 cells as evidenced by DNA laddering. These results suggest that type I/n=2 and type I/n=3 may be promising agents for the treatment of lung cancer and should be pursued in animal models.

A non-crosslinking platinum-acridine hybrid agent shows enhanced cytotoxicity compared to clinical BCNU and cisplatin in glioblastoma cells.

Using clonogenic survival assays, we demonstrated that a new platinum-acridine hybrid agent, PT-ACRAMTU, is cytotoxic in SNB19 and U87MG glioblastoma cells at low-micromolar concentrations. PT-ACRAMTU is more cytotoxic than ACRAMTU (the platinum-free acridine), acts in a time and dose dependent manner, and appears to generate an apoptotic response in both cell lines on the basis of increased caspase-3 activity.

Bis(acridinylthiourea)platinum(II) complexes: synthesis, DNA affinity, and biological activity in glioblastoma cells.

The preparation of two novel bis(acridine)platinum(II) complexes is reported. The 4+ charged conjugates associate strongly with double-stranded native DNA (K(i)>10(6)), possibly through bisintercalation. A cell viability assay was used to demonstrate that both compounds are capable of mediating cytotoxicity at micromolar concentrations in SNB19 brain tumor cells.

Structure-activity relationships in platinum-acridinylthiourea conjugates: effect of the thiourea nonleaving group on drug stability, nucleobase affinity, and in vitro cytotoxicity.

The synthesis, cytotoxicity, and nucleoside binding of some platinum-acridinylthiourea conjugates derived from the prototypical compound [PtCl(en)(ACRAMTU)](NO3)2 ("PT-ACRAMTU"; en=ethane-1,2-diamine, ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, protonated form) are reported. To establish structure-activity relationships within this class of compounds, systematic changes were made to the thiourea nonleaving group, which links the intercalator to platinum. Three new derivatives of ACRAMTU, one di-, one tri-, and one tetraalkylated, were generated, where the degree of alkylation indicates the number of alkyl groups attached to the SCN2 framework. Subsequent reaction of the tri- and tetraalkylated derivatives with activated [PtCl2(en)] yielded the corresponding platinum conjugates. The dialkylated thiourea gave an unstable complex, which was not included in the studies. The crystal structure of PT-ACRAMTU x MeOH has been determined. In the solid state, one axial position of the square-planar platinum coordination sphere is partially shielded by the bulky thiourea group, providing a strong rationale for the kinetic inertness of the compound. The cytotoxicity of the prototype, the two new conjugates, and cisplatin was assessed in ovarian (A2780, A2780/CP), lung (NCI-H460), and colon (RKO) cancer cell lines using clonogenic survival assays. The derivatives containing trialkylated thiourea groups showed activity similar or superior to cisplatin, with IC50 values in the low micromolar concentration range. The complex modified with the tetraalkylated (bulkiest) thiourea was significantly less active, possibly due to the greatly decreased rate of binding to nucleobase nitrogen (1H NMR spectroscopy), but was most efficient at overcoming cross resistance to cisplatin in A2780/CP. Possible consequences of the reported structural modifications for the mechanism of action of these agents are discussed.