Ritesh Rathore

Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model.

Purpose: Targeting epidermal growth factor receptor (EGFR) overexpressed by many epithelial-derived cancer cells with anti-EGFR monoclonal antibodies (mAb) inhibits their growth. A limited number of clinical responses in patients treated with the anti-EGFR mAb, (cetuximab), may reflect variability in EGFR type or signaling in neoplastic cells. This study combines EGFR-targeting with the non-MHC–restricted cytotoxicity of anti-CD3 activated T cells (ATC) to enhance receptor-directed cytotoxicity. Experimental Design: ATC from normal and patient donors were expanded ex vivo. Specific cytolytic activity of ATC armed with anti-CD3 × anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in 51Cr release assays. In vivo studies comparing tumor growth delay induced by EGFRBi-armed ATCs or cetuximab were done in severe combined immunodeficient/Beige mice (SCID-Beige) bearing COLO 356/FG pancreatic and LS174T colorectal tumors. Results: At effector/target ratios from 3.125 to 50, both EGFRBi-armed normal and patient ATC were significantly more cytotoxic, by 23% to 79%, against EGFR-positive cells over ATC, cetuximab, anti-CD3 alone, or ATC armed with irrelevant BiAb directed at CD20. EGFRBi-armed ATC also secreted significantly higher levels of some TH1/TH2 cytokines compared with ATC alone. In mice, i.v. infusions of EGFRBi-armed ATC (0.001 mg equivalent/infusion) were equally effective as cetuximab (1 mg/infusion) alone for significantly delaying growth of established COLO 356/FG but not LS174T tumors compared with mice that received ATC alone or vehicle (P < 0.001). Conclusions: Combining EGFR antibody targeting with T cell–mediated cytotoxicity may overcome some limitations associated with EGFR-targeting when using cetuximab alone.

Phase I trial of anti‐PSMA designer CAR‐T cells in prostate cancer: Possible role for interacting interleukin 2‐T cell pharmacodynamics as a determinant of clinical response

Chimeric antigen receptor (CAR)‐modified “designer” T cells (dTc, CAR‐T) against PSMA selectively target antigen‐expressing cells in vitro and eliminate tumors in vivo. Interleukin 2 (IL2), widely used in adoptive therapies, was proven essential in animal models for dTc to eradicate established solid tumors.

Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Purpose: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3–activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). Experimental Design: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 109 armed ATC (aATC) per infusion. Results: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 109 ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0–2+ patients. Conclusions: Targeting HER2+ and HER2− tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials. Clin Cancer Res; 21(10); 2305–14. ©2015 AACR.

Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients

Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 109 aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.

Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53)

A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer.

Phase I/II Study of Treatment of Stage IV Breast Cancer with OKT3 x Trastuzumab—Armed Activated T Cells

Rationale Metastatic breast cancer (MBC) is incurable with use of standard treatment modalities, with a median survival of 1-2 years after recurrence.1,2 Standard treatment regimens and high-dose chemotherapy with peripheral blood stem cell transplantation (HDC-SCT) have reached dose-limiting toxicities (DLTs) and are not curative for stage IV breast cancer. Therefore, nontoxic immunologic strategies are needed to improve overall survival (OS), progression-free survival (PFS), and quality of life of patients with stage IV disease. In an earlier phase II study, 23 women with stage IIIB/IV breast cancer were treated with HDC-SCT (n = 20) or dose-dense therapy (n = 3) followed by immunotherapy consisting of multiple infusions of anti-CD3 activated T cells (ATCs), lowdose interleukin (IL)–2, and granulocyte-macrophage colony-stimulating factor (GM-CSF).3 The OS rate was 70% and PFS was 50% at 30 months in the group that either received HDC-SCT or dose-dense therapy followed by immunotherapy, whereas 21 women in a historical control group treated with HDC-SCT without immunotherapy had an OS of 50% and a PFS of 15% (P = 0.09). These data suggest that specific targeting of ATCs would enhance an antitumor effect. One strategy is to arm ATCs with a bispecific antibody (BiAb) with specificity directed at CD3 (T-cell receptor) and HER2/neu, which redirects the nonspecific non–major histocompatibility complex (MHC)–restricted cytotoxicity exhibited by ATCs to target HER2-expressing tumors. We hypothesized that the targeting of ex vivo expanded T cells with anti-CD3 × anti-HER2/neu (ie, HER2BiAb) may thwart tumor escape, increase the frequency of tumor-specific cytotoxic T lymphocytes (CTLs), and immunize the patient against autologous breast cancer antigens. This article addresses the following preclinical questions Submitted: Mar 3, 2003; Revised: Apr 17, 2003; Accepted: Apr 15 , 2003 Address for correspondence: Lawrence G. Lum, MD, Roger Williams Hospital, North Campus, Room G01, 825 Chalkstone Ave, Providence, RI 02908 Fax: 401-456-2398; e-mail: llum@rwmc.org 1Immunotherapy and Blood and Stem Cell Transplantation Programs, Adele R. Decof Cancer Center 2Department of Radiation Oncology, Adele R. Decof Cancer Center, Roger Williams Medical Center 3Department of Pathology 4Department of Research Roger Williams Medical Center, Providence, RI 5Boston University School of Medicine, MA Phase I/II Study of Treatment of Stage IV Breast Cancer with OKT3 x Trastuzumab–Armed Activated T Cells

Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: a pilot study.

A pilot phase I clinical trial involving 15 infusions of anti-CD3 × anti-CD20 bispecific Ab (CD20Bi)-armed anti-CD3-activated T cells (aATC) and low-dose IL-2 was conducted in three non-Hodgkin’s lymphoma (NHL) patients (two high-risk and one refractory) after autologous SCT. The feasibility of T-cell expansion, safety of aATC infusions, cytotoxic immune responses and trafficking of aATC were evaluated. Three NHL patients received 15 infusions of 5 × 109 aATC (three infusions/week for 3 weeks and one infusion/week for 6 weeks) between days 1 and 65 after SCT with IL-2. There were no dose-limiting toxicities. Chills, fever, hypotension and malaise were the common side effects. Engraftment was delayed in one patient with a low stem cell dose. CD20Bi aATC infusions induced specific cytotoxicity directed at lymphoma targets. Endogenous peripheral blood mononuclear cells from two patients mediated anti-lymphoma cytotoxicity above preSCT background (P<0.001). 111In labeled aATC trafficked to the lungs at 1 h and accumulated in the liver and bone marrow after 24 h. aATC infusions given over 69 days in combination with IL-2 were safe, did not inhibit engraftment, and induced endogenous cytotoxic responses directed at lymphoma targets.

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis.

Objective:To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. Materials and Methods:Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Results:Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. Conclusion:Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer.

Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck.

ObjectiveTo perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. Patients and MethodsThirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m2) followed by concurrent weekly paclitaxel (40 mg/m2) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). ResultsThere was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. ConclusionsTherapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control.

Phase I study of hepatic arterial infusion of oxaliplatin in advanced hepatocellular cancer: a brown university oncology group study.

Purpose:We performed a phase I study to evaluate the feasibility and determine the maximally tolerated dose of hepatic arterial infusion (HAI) of oxaliplatin in advanced hepatocellular carcinoma (HCC). Patients and Methods:Patients with unresectable or recurrent HCC received HAI-oxaliplatin over 2 hours at dose escalation levels of 90, 110, 130, and 150 mg/m2 given every 3 weeks. The therapy was continued until disease progression or excessive toxicity not amenable to appropriate modifications. Restaging was performed after every 2 cycles. Results:A total of 23 patients were enrolled, with 17 patients evaluable for toxicity assessment. The median age was 63 years (range: 47–84 years), with 22 men and 1 woman. Stage distribution was as follows: stage II, 3 patients; stage III, 12 patients; and stage IV, 8 patients. A total of 53 cycles (range: 1–3) of HAI-oxaliplatin were delivered. The conventional grade 3/4 hematologic and gastrointestinal toxicities were infrequent. Among 17 evaluable patients receiving >2 cycles, 3 patients had partial responses and 8 had stable disease. A greater than 50% reduction in alphafetoprotein was seen in the 3 patients with partial responses and 3 patients with stable disease. Conclusions:HAI-oxaliplatin is a feasible, well tolerated, and demonstrated activity in this advanced HCC cohort. HAI-oxaliplatin 150 mg/m2 every 3 weeks was determined as the dose for further evaluation in phase II trials.