Enhanced T cell receptor specificity through framework engineering.

Development of T cell receptors (TCRs) as immunotherapeutics is hindered by inherent TCR cross-reactivity. Engineering more specific TCRs has proven challenging, as unlike antibodies, improving TCR affinity does not usually improve specificity. Although various protein design approaches have been explored to surmount this, mutations in TCR binding interfaces risk broadening specificity or introducing new reactivities. Here we explored if TCR specificity could alternatively be tuned through framework mutations distant from the interface. Studying the 868 TCR specific for the HIV SL9 epitope presented by HLA-A2, we used deep mutational scanning to identify a framework mutation above the mobile CDR3ß loop. This glycine to proline mutation had no discernable impact on binding affinity or functional avidity towards the SL9 epitope but weakened recognition of SL9 escape variants and led to fewer responses in a SL9-derived positional scanning library. In contrast, an interfacial mutation near the tip of CDR3α that also did not impact affinity or functional avidity towards SL9 weakened specificity. Simulations indicated that the specificity-enhancing mutation functions by reducing the range of loop motions, limiting the ability of the TCR to adjust to different ligands. Although our results are likely to be TCR dependent, using framework engineering to control TCR loop motions may be a viable strategy for improving the specificity of TCR-based immunotherapies.

Utilization of Autologous Hematopoietic Cell Transplantation Over Time in Multiple Myeloma: A Population-Based Study.

PURPOSE: Autologous hematopoietic cell transplantation (autoHCT) is associated with survival benefits in multiple myeloma (MM), but utilization remains low and differs by sociodemographic factors. Prior population-based studies have not fully captured autoHCT utilization or examined relationships between sociodemographic factors and autoHCT trends over time. PATIENTS AND METHODS: We used a novel data linkage between the California Cancer Registry, Center for International Blood and Marrow Transplant Research, and hospitalizations to capture autoHCT in a population-based MM cohort (n = 29, 109; 1991-2016). Due to interactions by treatment era, stratified multivariable Cox proportional hazards regression models determined factors associated with autoHCT. RESULTS: The frequency of MM patients who received autoHCT increased from 5.7% (1991-1995) to 27.4% (2011-2016). In models by treatment era, patients with public/no (vs. private) health insurance were less likely to receive autoHCT (2011-2016 Medicare hazard ratio (HR) 0.70, 95% confidence interval (CI): 0.63-0.78; Medicaid HR 0.81, CI: 0.72-0.91; no insurance HR 0.56, CI: 0.32-0.99). In each treatment era, Black/African American (vs. non-Hispanic White) patients were less likely to receive autoHCT (2011-2016 HR 0.83, CI: 0.72-0.95). Hispanic patients were less likely to undergo autoHCT, most prominently in the earliest treatment era (1991-1995 HR 0.58, 95% CI: 0.37-0.90; 2011-2016 HR 1.07, CI: 0.96-1.19). Patients in lower socioeconomic status neighborhoods were less likely to utilize autoHCT, but differences decreased over time. CONCLUSIONS: Despite increases in autoHCT utilization, sociodemographic disparities remain. Identifying and mitigating barriers to autoHCT is essential to ensuring more equitable access to this highly effective therapy.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Clinical characteristics, treatment patterns, and outcomes among African American and White patients with multiple myeloma in the United States.

Multiple myeloma (MM) is more common among Black/African American (AA) patients than White patients, but survival rate improvements are less pronounced for AA patients. This study evaluated treatment patterns and survival among 1810 AA and 5904 White adults in the United States with ≥1 MM treatment and ≥3 months of follow-up. Median time from diagnosis to systemic treatment was longer (37 [0-3053] vs. 35 [0-3664] days) and median time to stem cell transplant (SCT) was longer for AA than White patients (255 [1-2352] vs. 225 [1-3094] days), and AA patients were less likely to receive SCT (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.58-0.76). Despite disparities in treatment between AA and White patients, AA patients demonstrated lower risk of death (OR: 0.89; 95% CI: 0.81-0.96). These data highlight the value of equal access to care for the improvement of health outcomes in underserved populations.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

From mechanism to resistance - changes in the use of dexamethasone in the treatment of multiple myeloma.

Glucocorticoids, including dexamethasone, have been a mainstay of treatment for multiple myeloma (MM) for decades. In current treatment protocols and NCCN clinical practice guidelines, dexamethasone is included in all phases of MM treatment as a key adjunct to novel therapies within all preferred therapy regimen, augmenting clinical response rates to these agents. The inclusion of dexamethasone in MM treatment regimens, combined with novel agents, continues to deliver good response rates. Further understanding of drug combinations and dose modifications is anticipated to enhance clinical care, mitigate toxicities and optimize outcomes. New formulations are providing the opportunity for a reduction in pill burden and potential for medication errors, whereby improving treatment adherence. Here, we summarize and discuss the role of dexamethasone in the treatment of MM, its mechanism of action and doses used, and provide a critical appraisal current evidence and its clinical implications.

A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry.

MHC restriction, which describes the binding of TCRs from CD4+ T cells to class II MHC proteins and TCRs from CD8+ T cells to class I MHC proteins, is a hallmark of immunology. Seemingly rare TCRs that break this paradigm exist, but mechanistic insight into their behavior is lacking. TIL1383I is a prototypical class-mismatched TCR, cloned from a CD4+ T cell but recognizing the tyrosinase tumor antigen presented by the class I MHC HLA-A2 in a fully functional manner. Here we find that TIL1383I binds this class I target with a highly atypical geometry. Despite unorthodox binding, TCR signaling, antigen specificity, and the ability to use CD8 are maintained. Structurally, a key feature of TIL1383I is an exceptionally long CDR3ß loop that mediates functions that are traditionally performed separately by hypervariable and germline loops in canonical TCR structures. Our findings thus expand the range of known TCR binding geometries compatible with normal function and specificity, provide insight into the determinants of MHC restriction, and may help guide TCR selection and engineering for immunotherapy.

Clinical experience with frontline Hyper-CVAD-based regimens, including Hyper-CVAD plus ponatinib, in patients with acute lymphoblastic leukemia treated at a comprehensive cancer center.

BACKGROUND: Hyper-CVAD is an established regimen for adult ALL that was developed at the MD Anderson Cancer Center (MDACC). However, results can vary across different institutions given the heterogeneity of patient populations and institutional practices. Moreover, while a MDACC study demonstrated that the combination of ponatinib plus hyper-CVAD produced remarkable activity in untreated Ph+ ALL, it remains to be externally validated. We sought to validate those findings in previously untreated adult patients with Ph+ ALL. METHODS: This was a retrospective study analyzing the outcomes of previously untreated adult ALL patients treated with hyper-CVAD, with a focus on Ph+ ALL patients treated with ponatinib plus hyper-CVAD. RESULTS: 82 patients were included. The median age was 51 years. The median follow-up was 2.62 years. The 5-year overall survival (OS) and event-free survival (EFS) were 39.5 % and 28.2 %, respectively. For Ph+ ALL patients (n = 13) receiving ponatinib plus hyper-CVAD, 3-year OS and EFS were both 92.3 %. Univariate analysis showed a high WBC and poor-risk cytogenetics to be associated with inferior outcomes, while CD20 + predicted favorable outcomes in B-ALL patients. On multivariate analysis, CD20 + retained significance for Philadelphia-negative (Ph-) ALL. For Ph+ ALL, ponatinib was associated with better OS and EFS on univariate and multivariate analysis. CONCLUSION: Our data supports the use of ponatinib plus hyper-CVAD as a standard of care regimen for Ph+ ALL. Our outcomes for Ph-ALL and T-cell ALL (T-ALL) show that advances are still needed in the frontline setting, and clinical trial enrollment is recommended.

Engineering the T cell receptor for fun and profit: Uncovering complex biology, interrogating the immune system, and targeting disease.

T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. Due to the TCR's central role in immunity and tight connection with human health, there has been significant interest in modulating TCR properties through protein engineering methods. Complicating these efforts is the complexity and vast diversity of TCR-peptide/MHC interfaces, the interdependency between TCR affinity, specificity, and cross-reactivity, and the sophisticated relationships between TCR binding properties and T cell function, many aspects of which are not well understood. Here we review TCR engineering, starting with a brief historical overview followed by discussions of more recent developments, including new efforts and opportunities to engineer TCR affinity, modulate specificity, and develop novel TCR-based constructs.

Trust and shared decision-making among individuals with multiple myeloma: A qualitative study.

BACKGROUND: Multiple myeloma (MM) is an incurable cancer with complex treatment options. Trusting patient-clinician relationships are essential to promote effective shared decision-making that aligns best clinical practices with patient values and preferences. This study sought to shed light on the development of trust between MM patients and clinicians. METHODS: Nineteen individual semi-structured interviews were conducted with MM patients within 2 years of initial diagnosis or relapse for this qualitative study. Interviews were recorded and transcripts were coded thematically. RESULTS: We identified three main themes: (1) externally validated trust describes patients' predisposition to trust or distrust clinicians based on factors outside of patient-clinician interactions; (2) internally validated trust describes how patients develop trust based on interactions with specific clinicians. Internally validated trust is driven primarily by clinician communication practices that demonstrate competence, responsiveness, listening, honesty, and empathy; and (3) trust in relation to shared decision-making describes how patients relate the feeling of trust, or lack thereof, to the process of shared decision-making. CONCLUSION: Many factors contribute to the development of trust between MM patients and clinicians. While some are outside of clinicians' control, others derive from clinician behaviors and interpersonal communication skills. These findings suggest the possibility that trust can be enhanced through communication training or shared decision-making tools that emphasize relational communication. Given the important role trust plays in shared decision-making, clinicians working with MM patients should prioritize establishing positive, trusting relationships.

Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma.

PURPOSE: Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described. PATIENTS AND METHODS: We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies. RESULTS: At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes). CONCLUSIONS: Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.

Early outcomes of a modern cemented total knee arthroplasty : is tibial loosening a concern?

AIMS: Recent total knee arthroplasty (TKA) designs have featured more anatomical morphologies and shorter tibial keels. However, several reports have raised concerns about the impact of these modifications on implant longevity. The aim of this study was to report the early performance of a modern, cemented TKA design. METHODS: All patients who received a primary, cemented TKA between 2012 and 2017 with a minimum two-year follow-up were included. The implant investigated features an asymmetrical tibial baseplate and shortened keel. Patient demographic details, Knee Society Scores (KSS), component alignment, and the presence of radiolucent lines at final follow-up were recorded. Kaplan-Meier analyses were performed to estimate survivorship. RESULTS: A total of 720 of 754 primary TKAs (95.5%) were included with a mean follow-up of 3.9 years (SD 1.3); 562 (78.1%) were cruciate-retaining and 158 (21.9%) were posterior-stabilized. A total of 11 (1.5%) required reoperation for periprosthetic joint infection and seven (1.0%) for aseptic tibial loosening (five cruciate-retaining, two posterior-stabilized). Loosening occurred at a mean of 3.3 years (0.9 to 6.5). There were no cases of loosening in the 33 patients who received a 14 mm × 30 mm tibial stem extension. All-cause survivorship was 96.6% at three years (95% confidence interval (CI) 95.3% to 98.0%) and 96.2% at five years (95% CI 94.8% to 97.7%). Survivorship with revision for aseptic loosening was 99.6% at three years (95% CI 99.1% to 100.0%) and 99.1% at five years (95% CI 98.4% to 99.9%). Tibial components were in significantly more varus in those with aseptic loosening (mean 3.4° (SD 3.7°) vs 1.3° (SD 2.0°); p = 0.015). There were no other differences in demographic, radiological, or surgical characteristics between revised and non-revised TKAs for aseptic loosening (p = 0.293 to 1.00). Mean KSS improved significantly from 57.3 (SD 9.5) preoperatively to 92.6 (SD 8.9) at the final follow-up (p < 0.001). CONCLUSION: This is the largest series to date of this design of implant. At short-term follow-up, the rate of aseptic tibial loosening is not overly concerning. Further observation is required to determine if there will be an abnormal rate of loosening at mid- to long-term follow-up. Cite this article: Bone Joint J 2021;103-B(6 Supple A):51-58.

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center.

BACKGROUND: FLAG ± Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), is a salvage chemotherapy regimen for relapsed or refractory (R/R) acute myeloid leukemia (AML), with complete remission (CR) rates historically ranging from 52% to 63%. We review the outcomes for patients with R/R AML treated with FLAG ± Ida at the University of California Davis Comprehensive Cancer Center. PATIENTS AND METHODS: Adult patients (≥ 18 years) with R/R AML who received FLAG or FLAG + Ida from January 1, 2012 to October 31, 2016 were identified via chart review. Outcomes evaluated were CR, CR with incomplete hematologic recovery (CRi), overall response rate, overall survival (OS), relapse-free survival, and adverse events. RESULTS: Forty-two patients were included. The median age was 52 years (range, 23-73 years), and 57% were male. Sixteen (38.1%) patients had relapsed disease, and 26 (61.9%) had refractory disease. Most (n = 35; 83.3%) patients had European LeukemiaNet intermediate-risk AML. Responses were CR in 20 (47.6%) and CRi in 6 (14.3%). The median OS was 10 months (range, 0.8-51 months), and the median relapse-free survival was 12 months (range, 1-51 months) for responders. The median OS for patients who achieved CR was not reached, and the estimated 48-month survival rate was 56%. The median OS after CRi or no response was 3.47 and 2.17 months, respectively. The median OS was not significantly different when censored for stem cell transplant following chemotherapy, nor with use/deferral of idarubicin. The most common adverse effects were pancytopenia and infection. CONCLUSION: Patient outcomes after treatment with FLAG ± Ida for R/R AML remain similar to prior reports, confirming its role as a salvage regimen for these patients.

Outcomes of Adults With Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center.

Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8-24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.

Association of Morbid Progression With Overall Survival Among Patients With Multiple Myeloma: Validation of the Progression-free Survival Endpoint.

INTRODUCTION: Multiple myeloma (MM) is an incurable malignancy, marked by end-organ damage that is frequently irreversible. Progressive disease (PD) can be defined as morbid PD, associated with new-onset hypercalcemia, renal insufficiency, anemia, or lytic bone lesions (CRAB symptoms), or as asymptomatic biochemical progression. The frequency of morbid versus asymptomatic PD and its effect on survival is unknown. Our aim was to determine the incidence of morbid PD, and to evaluate if this influences survival. PATIENTS AND METHODS: Data from 2 phase III trials of transplant-ineligible patients with newly diagnosed MM were included in a post hoc analysis. RESULTS: Of 2082 patients enrolled, 1243 (59.7%) experienced PD. At first progression, 543 (43.7%) patients had morbid PD; 12 (2.2%) had hypercalcemia, 271 (49.9%) had renal insufficiency, 370 (68.1%) developed anemia, and 79 (14.5%) developed new or enlarged bone lesions. A total of 700 (56.3%) patients had asymptomatic PD. Patients with morbid PD had worse second progression-free survival (PFS) versus patients with asymptomatic biochemical PD (median second PFS, 11.5 months vs. 20.0 months; hazard ratio, 1.63; 95% confidence interval, 1.43-1.85; P < .0001) and worse overall survival (OS) (median OS, 23.2 months vs 39.3 months; hazard ratio, 1.51; 95% confidence interval, 1.30, 1.74; P < .0001). CONCLUSIONS: Morbid PD occurs frequently and is associated with inferior second PFS and OS. As CRAB symptoms may not reverse with therapy, morbid PD is a meaningful event, and its association with a shortened PFS adds validity to PFS as a relevant endpoint in patients with MM.

Second primary malignancies in multiple myeloma: A review.

As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.