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PURPOSE There is a need to refine the selection of patients with oropharyngeal squamous cell carcinoma (OPSCC) for treatment de-escalation. We investigated whether pretreatment absolute lymphocyte count (ALC) predicted overall survival (OS) benefit from the addition of concurrent chemotherapy to radical radiotherapy. PATIENTS AND METHODS This was an observational study of consecutive OPSCCs treated by curative-intent radiotherapy, with or without concurrent chemotherapy (n = 791) with external, independent validation from a separate institution (n = 609). The primary end point was OS at 5 years. Locoregional control (LRC) was assessed using competing risk regression as a secondary end point. Previously determined prognostic factors were used in a multivariable Cox proportional hazards model to assess the prognostic importance of ALC and the interaction between ALC and cisplatin chemotherapy use. RESULTS Pretreatment ALC was prognostic for 5-year OS on multivariable analysis (hazard ratio [HR] 0.64; 95% CI, 0.42 to 0.98; P = .04). It also predicted benefit from the use of concurrent cisplatin chemotherapy, with a significant interaction between cisplatin chemotherapy and pretreatment ALC (likelihood ratio test, P = .04): higher ALC count reduced the 5-year OS benefit compared with radiotherapy alone (HR 2.53; 95% CI, 1.03 to 6.19; P = .043). This was likely driven by an effect on LRC up to 5 years (interaction subdistribution HR 2.29; 95% CI, 0.68 to 7.71; P = .094). An independent validation cohort replicated the OS (HR 2.53; 95% CI, 0.98 to 6.52; P = .055) and LRC findings (interaction subdistribution HR 3.43; 95% CI, 1.23 to 9.52; P = .018). CONCLUSION For OPSCC, the pretreatment ALC is prognostic for OS and also predicts benefit from the addition of cisplatin chemotherapy to radiotherapy. These findings require prospective evaluation, and could inform the selection of good prognosis patients for a de-escalation trial.

Supplementary Figure 3 from Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Supplementary Figure 1 from Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Radioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using 131I-labeled anti–MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. 131I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry (∼1.0 Gy per MBq when 131I was labeled to 500 μg mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, 131I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of 131I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the 131I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of 131I-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioimmunotherapy of lymphoma. [Cancer Res 2007;67(3):1335–43]

Supplementary Figure 2 from Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.

Introduction: Hypoxia and an immunosuppressive tumor microenvironment (TME) are both independent negative prognostic factors that contribute to radiotherapy resistance in muscle-invasive bladder cancer (MIBC). Therefore, we sought to investigate the relationship between them and whether the immune TME can predict benefit from hypoxia-modifying therapy in the BCON trial that randomized MIBC patients to radiotherapy alone or with carbogen plus nicotinamide (CON). Methods: Tissue microarrays of diagnostic biopsies from 116 MIBC patients from the BCON trial were stained using Akoya Opal࣪ multiplex immunohistochemistry (IHC) reagents (CD8, CD4, FOXP3, CD68, PDL1, DAPI). Following multispectral scanning the slides were spectrally unmixed using Inform and marker proportion quantified using HALO software as the percentage of the total cell count per sample. Hypoxia was assessed as the presence of CA9 protein using IHC (n=111) and by using transcriptomic data (n=80) previously acquired to determine an hypoxia score (HS). Relationships with overall (OS) and local progression-free (LPFS) survival were assessed using Cox proportional hazard models and Kaplan-Meier curves in R. Molecular subtypes were determined using the consensusMIBC package in R. Results: Basal/squamous and stroma-rich vs other molecular subtypes had increased hypoxia scores and immune markers (CD8, CD4, CD68, PDL1). Tumors with CA9 present had significantly lower proportion of CD8 T cells (p=0.027), and CD4 T cells (p=0.01) but there were no significant differences for other immune markers or significant differences associated with HS. Only CD8 showed a relationship with survival and we found the relationship between log(HR) and CD8 to be non-linear, which led to placing patients within groups. Patients with a low vs high proportion of CD8 T cells had a significantly worse 2-year OS (n=116, p=0.003) and LPFS (n=116, p=0.02). CD8 proportion was also prognostic in patients receiving radiotherapy alone for OS (n=61; p=0.003) and LPFS (n=61; p=0.003). Patients with low CD8 T cells had improved OS when CON was given with radiotherapy (n=87; p=0.05), but those with high CD8 T cells derived no benefit (n=27; p=0.95). Prognostic significance of low CD8 T cells in the whole cohort remained after adjusting for clinicopathologic variables and hypoxia measured using CA9 (HR 0.32; 95% CI 0.18-0.57; p Conclusions: Low proportion of CD8 T cells in the TME of MIBC patients has independent prognostic and predictive value. It can be used to identify patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy. Citation Format: Vicky Smith, Debayan Mukherjee, Anna Maria Tsakiroglou, Alexander Baker, Hitesh Mistry, Ananya Choudhury, Peter Hoskin, Tim Illidge, Catharine West. Low CD8 T cells predicts benefit from hypoxia-modifying therapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6236.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Malignant lymphomas represent neoplasias arising from the peripheral lymphatic tissues in lymph nodes and extranodal sites. Classification in Hodgkin’s (HL) and non-Hodgkin’s lymphomas (NHL), B- or T-cell origin, nodal or extranodal involvement, and indolent or aggressive diseases gives a basic algorithm for clinical management. The introduction of positron emission tomography (PET) using 18F-Fluoro-deoxyglucose (18F-FDG) both alone or in combination with CT or MRI (PET/CT) improved accuracy of staging procedures and increasingly influence treatment algorithms. Current treatment options include classic cytotoxic drugs and radiotherapy and have been expanded by monoclonal antibodies, agents targeting signalling pathways and transplant procedures during the last two decades. Using this arsenal about 90% of patients with Hodgkin’s lymphomas and 60–80% of patients with aggressive B-NHL can be cured today.

Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. James's Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 50% of patients (pts) with sALCL develop recurrent disease after frontline treatment (Savage, 2008). Outcomes have historically been poor for pts with relapsed T-cell lymphomas, including sALCL, with a median overall survival (OS) and progression-free survival (PFS) of 5.5 months (mos) and 3.1 mos, respectively (Mak, 2013). A phase 2 study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Four-year follow-up data from this ongoing trial are presented. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. Response was assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, response is now being assessed per the investigator. Survival and disease status are being assessed every 3 mos for 2 years, every 6 mos during years 3 to 5, and annually thereafter. CT scans are required if progression is suspected clinically. Results: The enrolled population of 58 pts was heavily pretreated with poor prognosis. As previously reported, 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). Pts had received a median of 2 prior systemic chemotherapy regimens (range, 1 to 6). Per investigator, the objective response rate (ORR) with brentuximab vedotin was 83% (48 pts) and the CR rate was 62% (36 pts), which were similar to the previously reported ORR (86%) and CR (59%) rates per IRF. At the time of this analysis (data cut June 2014), all pts had discontinued treatment and the median observation time from first dose was 46.3 mos (range, 0.8 to 57.7). Sixty-two percent (36 of 58) of pts were alive at last follow-up and the estimated 4-year survival rate by Kaplan-Meier analysis was 64% (95% CI: 51%, 76%). Median OS by best clinical response was CR (n=36): median not reached; partial remission (n=12): 11.6 mos; stable disease (n=4): 6.9 mos; and progressive disease (n=2): 4.2 mos. Median PFS was 20.0 mos (95% CI: 9.4, – [range, 0.8 to 54.9+]) for all pts and was not reached in pts with CR. Median PFS for pts with ALK-positive (25.5 mos) and ALK-negative (20.0 mos) disease were similar. Median PFS for pts with PET-negative disease at Cycle 4 (n=28) was not reached, whereas median PFS for pts with PET-positive disease at Cycle 4 (n=20) was 6.7 mos. After discontinuing treatment, 18 pts received a hematopoietic SCT (9 allogeneic, 9 autologous). The median PFS for the pts who achieved a CR and did not receive a post-treatment SCT (n=21) was 37.7 mos (95% CI: 14.1, - [range, 2.8 to 51.1+]) and the median PFS was not reached for the pts who achieved a CR and received a subsequent SCT (n=15) (95% CI: 9.5, - [range, 8.0 to 54.4+]). Of the 36 pts who achieved CR per the investigator, 17 (47%) remain in follow-up free of progression: 10 pts received a consolidative SCT following treatment with brentuximab vedotin and 7 pts received no further therapy after completing brentuximab vedotin treatment. As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, and neutropenia. AEs ≥ Grade 3 that occurred in ≥5% of pts were neutropenia, thrombocytopenia, peripheral sensory neuropathy, anemia, recurrent ALCL, and fatigue. Conclusions: After a median observation time of approximately 4 years from first dose of brentuximab vedotin, the 4-year survival rate was 64%. Forty-seven percent of patients with CR remain in follow-up with no evidence of progression, suggesting that brentuximab vedotin treatment may be curative for some patients. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Figure 1 Figure 1. Disclosures Pro: Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Other, Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Other, Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Ramchandern:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding. Wang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Research Funding.

The aim of this study was to compare different dosimetric approaches on therapy naïve patients enrolled in a multicentre fractionated radioimmunotherapy trial, to determine which methodological approach correlates with bone marrow toxicity.Twenty-height non-Hodgkin lymphoma patients were treated with one or two fractions of 90Y-Ibritumomab-Tiuxetan (11.1 MBq/kg) 8 to 12 weeks apart in four different institutions. Quantitative imaging with 111In-Ibritumomab-Tiuxetan (185 MBq) was performed at 0, 1, 4 and 7 days after infusion, starting two weeks before the therapeutic administration. A whole-body (WB) CT scan was also acquired prior to the 111In-Ibritumomab injection, for attenuation correction purposes and was segmented to derive patient-specific organ masses. All dosimetry processing was centralized in a single institution. The first method (M_2D) was based on geometric mean WB scans, corrected for attenuation, scatter and organs superposition. The second method (M_2.5D) was based on the computed assisted matrix inversion approach and used segmented CT scans. The third method (M_3D) used iterative reconstruction of tomographic scans, corrected for attenuation, scatter and collimator response. Absorbed doses were estimated for lungs, liver, kidneys and spleen using MIRD S values adjusted for organ masses. Bone marrow (BM) absorbed doses were evaluated according to imaging methods (3) and compared to blood-based approaches.For some patients, organ masses such as liver or spleen significantly differed from male/female reference masses, whereas lungs and kidneys masses were relatively constant. Except for lungs, absorbed doses estimated by M_2D were higher than those from M_2.5D and these, in turn, were higher that those calculated from M_3D (Wilcoxon P8.6e-4). Median organ absorbed dose estimates were equivalent for both fractions except for the spleen. In fact, spleen absorbed doses for the second fraction were lower than those for the first fraction, regardless of the approach. Possible explanations are that patient spleen masses were kept constant for analysis of both fractions and/or that spleen uptake was lowered after the first fraction. Estimation of BM absorbed doses from blood sampling was unable to predict platelet toxicity, but image-based methods performed better. Additionally, for most organs, the absorbed dose delivered by the first fraction could predict that delivered by the second fraction.These results confirm that different acquisition/processing protocols will lead to statistically different absorbed doses. Additionally, image-based dosimetric approaches are needed in order to correlate absorbed dose to bone marrow toxicity.

Background Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented. Methods Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results In this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Conclusions After a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Disclosures: Pro: Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.

Despite the recent success of mAb in the treatment of certain malignancies, there is still considerable uncertainty about the mechanism of action of anti-cancer Abs. Here, a panel of rat anti-mouse B cell mAb, including Ab directed at surface IgM Id, CD19, CD22, CD40, CD74, and MHC class II, has been investigated in the treatment of two syngeneic mouse B cell lymphomas, BCL1 and A31. Only three mAb were therapeutically active in vivo, anti-Id, anti-CD19, and anti-CD40. mAb to the other Ags showed little or no therapeutic activity in either model despite giving good levels of surface binding and activity in Ag-dependent cellular cytotoxicity and complement assays, and in some cases inhibiting cell growth in vitro. We conclude that the activity of mAb in vitro does not predict therapeutic performance in vivo. Furthermore, in vivo tracking experiments using fluorescently tagged cells showed that anti-Id and anti-CD40 mAb probably operate via different mechanisms: the anti-Id mAb cause growth arrest that is almost immediate and does not eliminate cells over a period of 5 or 6 days, and the anti-CD40 mAb have a delayed effect that allows tumor to grow normally for 3 days, but then abruptly eradicates lymphoma cells. This work supports the belief that mAb specificity is critical to therapeutic success in lymphoma and that, in addition to any effector-recruiting activity they may possess, in vivo mAb operate via mechanisms that involve cross-linking and signaling of key cellular receptors.