The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma.

BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

Preventing sickness absenteeism among employees with common mental disorders or stress-related symptoms at work: Design of a cluster randomized controlled trial of a problem-solving based intervention versus care-as-usual conducted at the Occupational Health Services.

BACKGROUND: Common mental disorders (CMDs) are among the leading causes of sick leave in Sweden and other OECD countries. They result in suffering for the individual and considerable financial costs for the employer and for society at large. The occupational health service (OHS) can offer interventions in which both the individual and the work situation are taken into account. The aim of this paper is to describe the design of a study evaluating the effectiveness of an intervention given at the OHS to employees with CMDs or stress-related symptoms at work. In addition, intervention fidelity and its relation to the outcome will be assessed in a process analysis. METHODS: The study is designed as a cluster randomized trial in which the participating OHS consultants are randomized into either delivering the intervention or performing care as usual. Employees with CMDs or stress-related symptoms at work are recruited consecutively by the OHS consultants. The intervention aims to improve the match between the employee and the job situation. Interviews are held individually with the employee and the nearest supervisor, after which a joint meeting with both the employee and the supervisor takes place. A participatory approach is applied by which the supervisor and the employee are guided by the OHS consultant and encouraged to actively take part in problem solving concerning the work situation. Outcomes will be assessed at baseline and at six and 12 months. A long-term follow-up at 3 years will also be performed. The primary outcome is registered sickness absence during a 1-year period after study inclusion. Secondary outcomes are mental health and work ability. The intervention's cost effectiveness, compared to treatment as usual, both for society and for the employer will be evaluated. A process evaluation by both the OHS consultants and the employee will be carried out. DISCUSSION: The study includes analyses of the effectiveness of the intervention (clinical and economic) as well as an analysis of its implementation at the participating OHSs. Possible methodological challenges such as selection bias and risk of contamination between OHS consultants delivering the experimental condition and consultants giving usual care are discussed. TRIAL REGISTRATION: ClinicalTrials NCT02563743 Sep 28 2015.

Work-related stress assessed by a text message single-item stress question.

BACKGROUND: Given the prevalence of work stress-related ill-health in the Western world, it is important to find cost-effective, easy-to-use and valid measures which can be used both in research and in practice. AIMS: To examine the validity and reliability of the single-item stress question (SISQ), distributed weekly by short message service (SMS) and used for measurement of work-related stress. METHODS: The convergent validity was assessed through associations between the SISQ and subscales of the Job Demand-Control-Support model, the Effort-Reward Imbalance model and scales measuring depression, exhaustion and sleep. The predictive validity was assessed using SISQ data collected through SMS. The reliability was analysed by the test-retest procedure. RESULTS: Correlations between the SISQ and all the subscales except for job strain and esteem reward were significant, ranging from -0.186 to 0.627. The SISQ could also predict sick leave, depression and exhaustion at 12-month follow-up. The analysis on reliability revealed a satisfactory stability with a weighted kappa between 0.804 and 0.868. CONCLUSIONS: The SISQ, administered through SMS, can be used for the screening of stress levels in a working population.

Role of socio-cultural factors on changes in fitness and adiposity in youth: a 6-year follow-up study.

BACKGROUND AND AIMS: Optimal cardio-respiratory fitness and adiposity levels are tightly related to health in youth. We analysed changes in fitness and adiposity in young individuals from two countries, and examined the role of maternal education in these changes. METHODS AND RESULTS: A 6-year follow-up study was conducted on 483 Estonian children (9 years) and 466 Swedish children (9-10 years) and adolescents (15 years). Fitness was assessed by a maximal bike test, and total and central adiposity were indirectly estimated by skinfolds (Slaughter's equation for fat mass) and waist circumference. At follow-up, fitness and adiposity had increased in the children cohort (P ≤ 0.001), while small or no change occurred in the adolescent cohort. In the children cohort, Estonian participants had a lower increase in fitness and a higher increase in adiposity (total and central) than Swedish participants. Higher maternal education increased the odds of remaining fit (top quartile) by half and reduced the risk of remaining fat (top quartile) by half; odds ratios = 1.56 (1.00-2.43), 0.50 (0.32-0.77) and 0.61 (0.39-0.94) for fitness, total and central adiposity, respectively. CONCLUSIONS: Our data suggest that the socioeconomic situation of a country might influence key cardiovascular risk factors (fitness and adiposity), being at higher risk for a low-middle income country (Estonia) than a higher income country (Sweden). The findings stress the role of socioeconomic status, particularly maternal education, in the maintenance of healthy fitness and adiposity levels from childhood into later life. Preventive efforts have to be taken from early age.

A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder characterized by hyperuricemia and metabolic derangements. The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults. PATIENTS AND METHODS: We evaluated the efficacy of rasburicase (0.15 mg/kg) administered as single dose followed by as needed dosing (maximum five doses) versus daily dosing for 5 days in adult patients at risk for TLS. RESULTS: Eighty of the 82 patients enrolled received rasburicase; 40 high risk [median uric acid (UA) 8.5 mg/dl; range, 1.5-19.7] and 40 potential risk (UA = 5.6 mg/dl; range, 2.4-7.4). Seventy-nine patients (99%) experienced normalization in their UA within 4 h after the first dose; 84% to an undetectable level (<0.7 mg/dl). Thirty-nine of 40 (98%) patients in the daily-dose arm and 34 of 40 (85%) patients in single-dose arm showed sustained UA response. Six high-risk patients within the single-dose arm required second dose for UA >7.5 mg/dl. Rasburicase was well tolerated; one patient with glucose-6-phosphate dehydrogenase deficiency developed methemoglobinemia and hemolysis. CONCLUSIONS: Rasburicase is highly effective for prevention and management of hyperuricemia in adults at risk for TLS. Single-dose rasburicase was effective in most patients; only a subset of high-risk patients required a second dose.

Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.

Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma.

BACKGROUND: To determine the efficacy and side-effects of (90)Y ibritumomab tiuxetan (Zevalin) as front-line treatment in patients with early-stage extranodal indolent lymphoma of the ocular adnexa (orbit, conjunctiva, or eyelid). PATIENTS AND METHODS: From August 2004 to November 2007, 12 patients with stages I-E extranodal indolent lymphoma of the ocular adnexa were enrolled in a prospective trial of rituximab followed by (90)Y ibritumomab tiuxetan (Zevalin therapeutic regimen). For each patient, clinical examinations and imaging studies were used to document response to therapy using the The International Working Group response criteria. All patients had (111)In ibritumomab tixuetan imaging to confirm expected biodistribution before (90)Y-Zevalin therapy; in addition, three patients had an optional single photon emission computed tomography-computed tomography scan to estimate the absorbed radiation dose to the orbital and ocular tissues. RESULTS: The study included seven women and five men. The median age was 60 years (range 22-79). Nine patients had mucosa-associated lymphoid tissue lymphoma of conjunctiva or orbit; three patients had grades 1-2 follicular lymphoma of orbit. One patient who had been deemed stage I-E initially was found to have another lesion in her deltoid muscle on positron emission tomography 2 weeks after enrollment. She was kept on trial although her disease was reclassified as stage IV due to this single additional (biopsy-proven) site. Ten patients had a complete response and two partial response (PR) within 3 months of treatment. One patient had a recurrence in the upper eyelid 6 months after an initial PR; he then received 30 Gy of external-beam radiotherapy (EBRT). His disease later progressed again in the orbit and he is currently being considered for other treatments. A second patient who attained a PR has remained stable with no progression 12 months after treatment. With a median follow-up time of 20 months (range 6-44 months), there were no cases of distant (extraorbital) relapse. All 12 patients experienced grade I or II transient pancytopenia during the first 3 months after enrollment in the trial. There were no episodes of grade III or IV myelosuppression. The estimated absorbed radiation dose to the orbital soft tissues was <3 Gy, 10 times lower than that with EBRT. CONCLUSIONS: Rituximab followed by (90)Y ibritumomab tiuxetan is an effective and safe front-line treatment for early-stage extranodal indolent B-cell lymphoma of the ocular adnexa.

H-2-linked resistance to mastocytoma in male mice: immune response to a histocompatibility antigen on the X chromosome.

Male hybrids from a cross between female mice of strain C57BL/6Kh and males of strain DBA/2J lived longer after injection of P815 mastocytoma cells of DBA/2 origin than did their female siblings. Responses to the histocompatibility antigen on the X chromosome of the DBA/2 strain may be involved in resistance to the tumor. When the female parent was replaced with a C57BL/6Kh carrying one of several mutations in the H-2 region, this sex effect disappeared in some of the hybrid combinations. Thus, the H-2 complex appears to be involved in the regulation of the immune response to the X-linked histocompatibility antigen in this tumor model.

The addition of rituximab to CHOP chemotherapy improves overall and failure-free survival for follicular grade 3 lymphoma.

BACKGROUND: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied. PATIENTS AND METHODS: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made. RESULTS: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk. The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034. CONCLUSION: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.

The NHF-NRG In Balance-project: the application of Intervention Mapping in the development, implementation and evaluation of weight gain prevention at the worksite.

Very few examples of theory-driven and systematically developed weight gain prevention interventions for adults have been described in the literature. The present paper systematically describes the development, implementation and evaluation framework of a weight gain prevention programme directed at young adults at the worksite, namely the NHF-NRG In Balance-project. It not only can be used as a guide to systematically develop weight gain prevention interventions, but also gives an overview of the current theoretical and empirical knowledge-base in the field of obesity prevention. The outline of the paper follows the Intervention Mapping protocol, which includes a systematic inventory of important health issues, their risk behaviours and determinants of these risk behaviours, and specification of the proximal objectives of the programme directed at both energy intake and energy expenditure. The objectives are translated into behaviour change methods and strategies, which are combined in a stepwise intervention programme, and used for a detailed evaluation plan (process and effect evaluation). The NHF-NRG In Balance-project combines mass media and individually tailored communications with worksite environmental changes to raise awareness, to motivate and to enable energy balance behaviour changes. A quasi-experimental pre-test-multiple post-test control group design was applied in 12 worksites (>500 employees).

Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity.

We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.

Tumor antigen-specific immunization of bone marrow transplantation donors as adoptive therapy against established tumor.

BACKGROUND: Persistence of the underlying malignancy remains the main obstacle to the successful treatment of human malignancies with high-dose chemoradiotherapy and bone marrow transplantation. PURPOSE: The aim of this study was to determine whether antigen-specific antitumor immune responses, elicited in normal donor mice by immunization with the soluble form of a surrogate tumor antigen (i.e., ovalbumin [OVA]), can be transferred via bone marrow transplantation into lethally irradiated, syngeneic recipient mice. An additional goal was to evaluate the ability of these adoptively transferred bone marrow cells to eradicate established recombinant OVA-expressing lymphomas that recurred after lethal-dose total-body irradiation (TBI). METHODS: Female C57BL/6 donor mice were immunized twice with OVA emulsified in a muramyl-dipeptide-containing adjuvant. Syngeneic mice bearing a day-10 or day-11, approximately 1-cm subcutaneous E.G7-OVA tumor (E.G7-OVA tumor cells were derived from transfection of EL-4 thymoma tumor cells using the coding sequence of chicken OVA gene complementary DNA) were treated with TBI and reconstituted with bone marrow from nonimmune or OVA-immunized mice. In subsequent experiments, tumor-bearing mice, treated with TBI and OVA-immune bone marrow, were given additional therapy either with a single OVA immunization or by the adoptive transfer of 1 x 10(7) in vitro activated spleen cells derived from OVA-immune donor mice and cultured 5 days with irradiated E.G7-OVA cells before transfer. RESULTS: E.G7-OVA tumor-bearing mice given TBI and OVA-immune bone marrow showed a significantly increased cure rate when compared with that among controls reconstituted with nonimmune bone marrow after TBI (logrank, P < .01). The antitumor effect of immune bone marrow was abrogated by T-cell depletion of the marrow graft (P < .016). The antitumor effect of immune marrow was enhanced by the addition of OVA immunization of tumor-bearing recipients (P < .015). OVA-specific cytotoxic T-lymphocyte (CTL) activity was recovered from tumor-bearing recipients of immune marrow 14 days after bone marrow transplantation. The antitumor effect observed following the adoptive transfer of immune marrow was further augmented by the addition of 1 x 10(7) splenic E.G7-OVA-specific in vitro activated CTLs derived from OVA-immune mice (P < .03). CONCLUSION: These studies establish the principle that antigen-specific T-cell immunity against a defined tumor-specific antigen can be transferred with bone marrow from an immune donor. IMPLICATIONS: Active immunization of normal human bone marrow or T-cell donors with a refined, safe tumor antigen and transfer of immunity to the patient may represent a novel strategy for circumventing the obstacle of host immune suppression associated with the tumor-bearing state.

Cytotoxic T-cell response and in vivo protection against tumor cells harboring activated ras proto-oncogenes.

BACKGROUND: Activated forms of the ras proto-oncogene have been found in approximately 30% of human malignancies, including pancreatic, colon, and lung adenocarcinomas. Ras oncoproteins arise by somatic mutation and contain amino acid changes at residues 12, 13, or 61, thus generating unique tumor-specific proteins that are attractive targets for cancer therapy. PURPOSE: The goal of this study was to determine whether vaccination with mutant Ras protein could lead to the generation of cytotoxic T lymphocytes (CTLs) specific for the mutant epitope and to protection against challenge with tumor cells expressing the mutant oncoprotein. METHODS: To determine a methodology for generating CTL responses following immunization with soluble protein, ovalbumin was used as a model tumor antigen. C57BL/6 mice were immunized with soluble ovalbumin administered intraperitoneally at 2-week intervals or with intravenous injection of ovalbumin or osmotically loaded splenocytes. Immunized mice were challenged with E.G7 cells (which express a transfected ovalbumin gene), and tumor growth was monitored. Generation of ovalbumin-specific CTLs was determined by 51Cr release assays. Purified wild-type or mutant H-Ras proteins (containing single amino acid substitutions at position 12 converting Gly to Arg or Val) were used to immunize BALB/c mice intraperitoneally. Ras-immunized mice were challenged with tumor cells containing Arg 12 or Val 12 mutations or not harboring mutant forms of Ras. Cytolytic and proliferative responses to mutant forms of Ras were studied, and the effects of in vivo depletion of CD4+ or CD8+ T lymphocytes were determined. RESULTS: In vivo challenge with E.G7 showed that intraperitoneal immunization with soluble ovalbumin was as effective as osmotic loading, resulting in long-term disease-free survival of some mice and the development of ovalbumin-specific CTLs. Immunization with Arg 12 Ras led to disease-free survival in nine of 10 animals challenged with tumor cells containing an Arg 12 mutation, while no protection was afforded against tumors expressing other forms of Ras or other oncogenes. Splenocytes from BALB/c mice immunized with Arg 12 Ras demonstrated cytolytic activity specific against tumor cells expressing Arg 12 Ras, with most of this activity residing in the CD8+ subset. Mutation-specific proliferation to Arg 12 Ras peptides was also observed. Immunization with Val 12 Ras did not elicit detectable Val 12-specific immunity. CONCLUSIONS: Antigen-specific CTLs can be induced following intraperitoneal immunization of mice with purified, soluble proteins. For both ovalbumin and Arg 12 Ras, specific in vivo protection against tumor cell challenge was observed.

Tumor resistance induced by syngeneic bone marrow transplantation and enhanced by interleukin 2: a model for the graft versus leukemia reaction.

Lethally irradiated C3H/HeN mice reconstituted with normal syngeneic bone marrow survived significantly longer than unmanipulated control mice following challenge with a lethal dose of 38C13 lymphoma cells 2 to 3 weeks post-bone marrow transplantation (BMT). Although the magnitude of this effect was modest, it was highly reproducible. This resistance-producing effect of BMT could be enhanced by interleukin 2 administration and could be abrogated by anti-asialo-GM1 antiserum treatment of recipients. These findings are consistent with the hypothesis that cells with a natural killer phenotype are activated by BMT and can mediate tumor resistance. These studies provide a model to explore the cellular basis, independent of donor alloreactivity, of the graft antitumor effect of BMT observed in humans.

H-2 gene control of resistance to P815-X2 mastocytoma.

Some, but not all, mutations at H-2 loci can alter, in either direction, histocompatible tumor resistance in the model system of P815-X2 mastocytoma (DBA/2 origin) transplanted into DBA/2J or (C57BL/6 X DBA/2J)F1 mice. This hybrid effect has been shown previously to depend on the immune system. We have examined eight mutants at H-2Kb (bm1, bm4, bm6, bm7, bm8, bm10, bm11, and bm16, two at H-2Db (bm13 and bm14), and one I-Ab mutant (bm12). When one parent is an H-2b mutant (C57BL/6 mutant), the hybrid progeny (C57BL/6 mutant X DBA/2J)F1 may have increased (bm7 and bm8) or decreased (bm10, bm11, bm12, and bm16) survival times when compared to C57BL/6 X DBA/2J)F1 controls. Hybrids from bm1, bm4, bm6 (all H-2Kb), and bm13 and bm14 (both H-2Db) mutants showed no differences in survival. Several of the mutant molecules differ from those of the parental strain by only one or two amino acids. Apparently, these small changes in H-2 antigens are capable of altering resistance to a histocompatible tumor to produce an immune response gene-like effect. The availability of H-2 mutant strains and detailed data on the molecular nature of the gene products make the model presented in this report a particularly useful system to study.

Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis.

While diffuse large-cell lymphoma (DLCL) is considered to be highly curable with current therapy, treatment failures are observed even with intensive combination chemotherapy regimens. In order to study the prognostic significance of actual dose intensity of chemotherapy in DLCL, we retrospectively analyzed 115 previously untreated patients treated as Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclosphosphamide, vincristine, prednisone, and bleomycin (MACOP-B). The actual relative dose intensity (RDI), the amount of drug actually administered to each patient during the first 12 weeks of therapy, was calculated as standardized to CHOP and analyzed in addition to clinical factors prognostic for survival by univariate analysis. Multivariate recursive partitioning (tree-structured) survival analysis identified the actual RDI of Adriamycin greater than 75% as the single most important predictor of survival. A model incorporating the actual RDI of Adriamycin and performance status, in combination with serum lactate dehydrogenase (LDH) and extranodal disease, defined three overall prognostic groups of patients with respective 3-year survival rates of 89%, 63%, and 18%. The three prognostic groups remained distinct, even when restricted to complete responders. This model was also predictive of survival when dose intensity was analyzed relative to the optimum dose defined for each of the three regimens and when applied to a subgroup of patients aged 50 years or younger. We conclude that actual RDI is an important prognostic factor for survival in DLCL and that analysis of RDI early in the course of treatment may allow modification of the treatment plan.

Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience.

Although previous studies have suggested a relatively poor prognosis for some patients with peripheral T-cell lymphoma, the clinical significance of immunologic phenotype in diffuse large-cell lymphoma (DLCL) remains controversial. One hundred one patients with a uniform morphologic diagnosis of DLCL treated at Stanford between 1975 and 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), vincristine, and prednisone (CHOP), methotrexate, bleomycin, Adriamycin, cyclophosphamide, vincristine, and dexamethasone ([M]BACOD), or methotrexate, Adriamycin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) chemotherapy were studied with regard to immunologic phenotype. Immunologic analysis, performed on frozen or paraffin-embedded tissue, identified 77 cases of B-cell origin, 21 cases of T-cell origin, and three cases that lacked B-cell or T-cell markers. Analysis of complete remission (CR) rates (84% v 95%), 5-year actuarial freedom from disease progression (38% v 53%), and 5-year actuarial overall survival (52% v 79%) showed no statistically significant differences in prognosis between B- and T-cell patients, respectively. The 5-year actuarial survival of patients with stage IV T-cell DLCL (56%) also did not differ in a statistically significant way from stage IV B-cell patients (36%). We conclude that treatment selection for DLCL should not be based on immunologic phenotype alone.

Clinical trial designs for the early clinical development of therapeutic cancer vaccines.

There are major differences between therapeutic tumor vaccines and chemotherapeutic agents that have important implications for the design of early clinical trials. Many vaccines are inherently safe and do not require phase I dose finding trials. Patients with advanced cancers and compromised immune systems are not good candidates for assessing either the toxicity or efficacy of therapeutic cancer vaccines. The rapid pace of development of new vaccine candidates and the variety of possible adjuvants and modifications in method of administration makes it important to use efficient designs for clinical screening and evaluation of vaccine regimens. We review the potential advantages of a wide range of clinical trial designs for the development of tumor vaccines. We address the role of immunological endpoints in early clinical trials of tumor vaccines, investigate the design implications of attempting to use disease stabilization as an end point and discuss the difficulties of reliably utilizing historical control data. Several conclusions for expediting the clinical development of effective cancer vaccines are proposed.