Durable Disease Remission Research Articles

T cell responses to tumor associated antigens in multiple myeloma patients treated with MV-NIS, an oncolytic measles virus.

218 Background: Evidence from mouse studies shows that Oncolytic viral mode of tumor cell killing can boost the cytotoxic T lymphocyte response against tumor associated antigens (TAA), leading to ‘bystander’ killing of uninfected tumor cells. Methods: To investigate whether oncolytic virotherapy can boost immune responses to tumor antigens in human subjects we studied T cell responses to 10 different TAA reported to have high expression in patients with multiple myeloma (n = 10) before and after intravenous administration of an oncolytic measles virus (MV-NIS). Baseline and 6 week post-therapy PBMC samples were stimulated with peptides specific to each of the selected TAA and their responses to this antigenic stimulation were measured using IFNγ ELISPOT. Results: Despite their prior exposure to multiple immunosuppressive treatment regimens, some of the tested patients had higher T cell responses to some of the TAA even prior to MV-NIS. Baseline T cell responses against MAGEc1 were present in 50% of the patients, and against hTERT and NYESO-1 in 30% of the patients. Furthermore, MV-NIS treatment significantly boosted T cell responses against NYESO-1, MAGEc1, MAGEA1 and MUC1 in 40% of the patients. Interestingly, in one outlier patient who achieved a stringent and durable complete disease remission after MV-NIS therapy, strong baseline T cell responses were present against 8 of the 10 tested TAA but did not change significantly after virotherapy. Based on the T cell responses to the TAA, three distinct phenotypes can be identified. Phenotype 1 was characterized by positive T cell responses to TAA prior and post therapy, Phenotype 2 was characterized by positive T cell responses to TAA only post therapy and phenotype 3 was characterized by negative T cell responses to TAA prior and post therapy. Conclusions: Our data suggests oncolytic measles virotherapy boosted the cytotoxic T lymphocyte response against tumor associated antigens in some of the patients. Identifying patient’s phenotype based on responsiveness to the TAA could be useful marker for identifying the immune responsive state in multiple myeloma patients and identify patients who can be most responsive to oncolytic measles virotherapy. Clinical trial information: NCT00450814.

Harnessing the CD1 restricted T cell response for leukemia adoptive immunotherapy

Disease recurrence following chemotherapy and allogeneic hematopoietic cell transplantation is the major unmet clinical need of acute leukemia. Adoptive cell therapy (ACT) with allogeneic T lymphocytes can control recurrences at the cost of inducing detrimental GVHD. Targeting T cell recognition on leukemia cells is therefore needed to overcome the problem and ensure safe and durable disease remission. In this review, we discuss adoptive cells therapy based on CD1-restricted T cells specific for tumor associated self-lipid antigens. CD1 molecules are identical in every individual and expressed essentially on mature hematopoietic cells and leukemia blasts, but not by parenchymatous cells, while lipid antigens are enriched in malignant cells and unlike to mutate upon immune-mediated selective pressure. Redirecting T cells against self-lipids presented by CD1 molecules can thus provide an appealing cell therapy strategy for acute leukemia that is patient-unrestricted and can minimize risks for GVHD, implying potential prognostic improvement for this cancer.

AT-22ALISERTIB MONOTHERAPY IN THE TREATMENT OF RELAPSED ATYPICAL TERATOID RHABDOID TUMOR (ATRT)

AT-22. ALISERTIB MONOTHERAPY IN THE TREATMENT OF RELAPSED ATYPICAL TERATOID RHABDOID TUMOR (ATRT) Magimairajan Issai Vanan1, Patrick McDonald2, Colin Kazina3, Junliang Liu1, Sherry Krawitz4, Martin Bunge5, Annie Ong1, and Brent Orr6; CancerCare Manitoba/Winnipeg Children’s Hospital, Winnipeg, MB, Canada; Pediatric Neuro-surgery/BC Children’s Hospital, Vancouver, BC, Canada; Pediatric Neuro-Surgery/University of Manitoba, Winnipeg, MB, Canada; Neuropathology/University of Manitoba, Winnipeg, MB, Canada; Radiology/University of Manitoba, Winnipeg, MB, Canada; Pathology/ St Jude Children’s Research Hospital, Memphis, TN, USA Atypical teratoid rhabdoid tumors (ATRTs) account for up to 20% of brain tumors in children less than 3yrs of age. The overall prognosis of ATRTs is extremely poor with median survival in the range of 10-18mths from the time of diagnosis. Aurora A Kinase (AURKA) encodes a protein that regulates the formationandstabilityof themitotic spindleand ishighlyactive inATRTthrough loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) is a selective small molecule inhibitor of AURKA. We report a case of recurrent ATRT treated with alisertib monotherapy producing sustained and durable disease remission. Our patient underwent gross total resection (GTR) of the Posterior fossa tumor at diagnosis and was initially treated as per ACNS0333 protocol. She remained in remission for 15 months after completion of chemotherapy when she relapsed in the right frontal lobe. She underwent sub-total resection (STR) followed by focal IMRT (54Gy/30 fractions) followed by chemotherapy (DFCI-IRS-III, modified protocol) with Doxorubicin / Etoposide alternating with Actinomycin-D and triple intrathecal chemotherapy. After 7 months of treatment, she relapsed again in the right frontal region, presenting with focal seizures. She received 10 cycles of alisertib (60mg/m2 by mouth once daily for 7 days of a 21 day treatment cycle) monotherapyand is clinically stablewith her imaging showingsustained regression of disease. Somnolescence and neutropenia were the most common side effects seen in our patient. Neuro-Oncology 18:iii1–iii6, 2016. doi:10.1093/neuonc/now065.21 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A Focus on IL-17 Targeting Treatments in Psoriasis

Psoriasis is a frequent and chronicle disease of the skin and less often of the joint that associates erythema, keratinizing troubles and inflammatory phenomenon. Usually benign, it can severely impacts quality of life in patients suffering from severe forms. Appearing in 2005, biotherapies like Tumor Necrosis Factor alpha inhibitors have permitted outstanding clinical response and brought patients the hope of durable disease remission. Nevertheless, treatments efficacy tends to decrease over time leading to symptoms relapsein many patients, for which new treatment targets have been needed.Recent advances in molecular biology, and genetics, have allowed the characterization of a distinct subtype of T helper lymphocyte found as infiltrates surrounding the capillaries in the dermis and the epidermis in psoriasis-presenting patients. These Th17 helper cells express and secrete a pro-inflammatory cytokine called interleukin 17,which play a key-role in inflammation and psoriasis pathophysiology. Therefore, molecules interfering with this pathway have been studied intensively;the purpose of this review is to report the results of such strategy. Keywords: psoriasis, inflammation, interleukin 17, interleukin 17-inhibitors

The Metaboloepigenetic Dimension of Cancer Stem Cells: Evaluating the Market Potential for New Metabostemness-Targeting Oncology Drugs.

The current global portfolio of oncology drugs is unlikely to produce durable disease remission for millions of cancer patients worldwide. This is due, in part, to the existence of so-called cancer stem cells (CSCs), a particularly aggressive type of malignant cell that is capable of indefinite self-replication, is refractory to conventional treatments, and is skilled at spreading and colonizing distant organs. To date, no drugs from big-league Pharma companies are capable of killing CSCs. Why? Quite simply, a classic drug development approach based on mutated genes and pathological protein products cannot efficiently target the plastic, epigenetic proclivity of cancer tissues to generate CSCs. Recent studies have proposed that certain elite metabolites (oncometabolites) and other common metabolites can significantly influence the establishment and maintenance of epigenetic signatures of stemness and cancer. Consequently, cellular metabolism and the core epigenetic codes, DNA methylation and histone modification, can be better viewed as an integrated metaboloepigenetic dimension of CSCs, which we have recently termed cancer metabostemness. By targeting weaknesses in the bridge connecting metabolism and epigenetics, a new generation of metabostemnessspecific drugs can be generated for potent and long-lasting elimination of life-threatening CSCs. Here I evaluate the market potential of re-modeling the oncology drug pipeline by discovering and developing new metabolic approaches able to target the apparently undruggable epigenetic programs that dynamically regulate the plasticity of non-CSC and CSC cellular states.

96IN - Clinical Interpretation of Response with Immunotherapy

ABSTRACT In the past 4 years immunotherapy of cancer has become an approved strategy for the treatment of human cancer. Sipuleucel-T was approved for CRPC (1) and ipilimumab has been approved for the treatment of MM (2,3). Because of very promising results with PD1/PD-L1 blockade in MM, mRCC and NSCLC, chances that these drugs will become approved in the near future are high(4-6). Targeting CTLA4 or PD1/PD-L1 work at the interaction between antigen presenting cells or tumor cells and T-cells. This may shift the balance from an ineffective to an affective T-cell immune response. Whereas for classical cytotoxic drugs and targeted agents objective response rates and progression free survival indicate the efficacy of the treatment, this is much less the case for immunotherapy. The major benefit for immunotherapy lies in inducing long-term responses (CR, PR and SD) in patients. These responses can develop over prolonged periods of time, and patients may show disease progression early on, followed by regression or disease stabilization later. Therefore, the classical criteria to measure responses (RECIST or WHO) sometimes fail to assess the clinical benefit patients experience from immunotherapy. Based on this short-coming, immune-related Response Criteria (irRC) have been proposed that allow continuation of treatment in clinical trials despite signs of unresponsiveness or mixed effects at first evaluation. The currently so oftentimes demonstrated swimmer plots for PD1/PD-L1 blockade demonstrate that objective responses can develop over time (7). By stopping treatment too early, the postponed clinical responses observed in patients treated with immunotherapy, may be missed, depriving the patients from a potentially effective or even durable disease remission. In conclusion, clinical interpretation of response to immunotherapy requires the implementation of specific immune related response criteria to allow continuation of treatment beyond early disease progression. 1. Kantoff PW, et al. N Engl J Med. 2010;363:411–22. 2. Hodi FS, et al. Engl J Med. 2010;363:711–23. 3. Robert C, et al. N Engl J Med. 2011;364:2517–26. 4. Topalian SL, et al. N Engl J Med. 2012;366:2443–54. 5. Brahmer JR, et al. N Engl J Med. 2012;366:2455–65. 6. Hamid O, et al. N Engl J Med. 2013;369:134–44. 7. Wolchok JD, et al. Clin Cancer Res 2009;15:7412–20. Disclosure: J.B.A.G. Haanen: Received research grant from BMS Consultancy role for BMS, Merck, Roche, GSK.

Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.

Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.

Multiple Successful Desensitizations to Brentuximab Vedotin: A Case Report and Literature Review

Brentuximab vedotin is an antibody-drug conjugate FDA-approved for the treatment of systemic anaplastic large-cell lymphoma (ALCL) that has relapsed after multiagent chemotherapy. At least 2 cases of hypersensitivity reactions to brentuximab vedotin have been reported, without attempted desensitization. This report describes a morbidly obese 32-year-old woman with ALCL that relapsed after autologous stem cell transplantation, who was treated on a phase II clinical study with brentuximab vedotin. After 1 dose, she experienced near-complete remission, but therapy was stopped because of severe drug-related toxicity. She then received 5 cytotoxic treatments and radiation, and ultimately experienced disease progression. The patient was rechallenged with brentuximab vedotin approximately 28 months after initial exposure and tolerated the dose well, but experienced a significant allergic reaction with the next dose. High-dose steroid and antihistamine prophylaxis administered 50 minutes before the subsequent brentuximab vedotin infusion was unsuccessful in mitigating this reaction. Brentuximab vedotin was successfully infused according to a rapid desensitization protocol. With progressive dose titration and supportive care, the patient tolerated this therapy. She received 11 doses through a rapid desensitization protocol and experienced a durable disease remission.

The impact of high-intensity conditioning prior to allogeneic stem cell transplantation in patients with chemorefractory or relapsed T-cell lymphoma.

8040 Background: Patients with relapsed T-cell lymphoma carry a particularly dismal prognosis. Optimal therapeutic strategies are yet to be defined. However, emerging evidence suggests a pivotal role of allogeneic stem cell transplantation in this situation. Methods: Between 2003 and 2011, allogeneic peripheral blood stem cell transplantation (PBSCT) from matched related (MRD, n=23) and matched unrelated (MUD, n=33) donors had been provided to 66 consecutive patients with refractory or relapsed aggressive T-cell malignancies, comprising cases of peripheral T-cell lymphomas not otherwise specified (PTCL NOS, n= 23), PTCL AILT (n=12), anaplastic large cell lymphoma (ALCL, n= 11), T-lymphoblastic lymphoma (T-LBL, n=6), T-prolymphocyctic leukemia (T-PLL, n=7), CD4+/CD56+ blastic plasmacytoid DC neoplasm (DPCL, n=2), panniculitis like T-cell lymphoma (PLTCL, n=3), systemic progression of primary cutaneous T-cell lymphoma (CTCL, n=1) and NK/T-cell lymphoma (n=1). Preparatory therapy consisted of high intensity conditioning, mainly consisting of the FBC-12 regimen (fludarabine 125 mg/m2, busulfan 12 or 8 mg/kg, cyclophosphamide 120 mg/kg). Results: Transplantion related mortality at day 100 occurred in 19/66 (29%) patients (pts). After a median observation of 12 (range 1 to 86) months, 48% and 46% pts were alive and disease-free, respectively. Ten pts experiencing disease relapse after allogeneic stem cell transplantation received donor lymphocyte infusions, resulting in complete remission in 5 pts, partial remission in one pt and progressive disease in 4 pts. DLI was associated with GvHD in all pts, leading to GvHD-associated deaths in CR in two pts. Three pts with relapse after allogeneic SCT achieved long-term remissions (> 12 months) by DLI. Conclusions: We conclude that allogeneic PBSCT following high-intensity conditioning induces durable disease remission in significant proportions of patients with relapsed or refractory aggressive T-cell malignancies. Post transplantation DLI may contribute to disease control, albeit at risk of severe GvHD.

Successful treatment of renal AA amyloidosis in familial Mediterranean fever with pegylated alpha-2a interferon

Renal AA amyloidosis is a severe consequence of chronic inflammatory diseases such as familial Mediterranean fever (FMF). FMF is caused by mutations in the MEFV gene, resulting in defective control of granulocyte-mediated inflammation. Interferon-alpha is known to induce MEFV expression in monocytes and granulocytes in vitro. We present the first case of colchicine-resistant FMF in which a durable disease remission and regression of renal amyloidosis was induced by chronic treatment with pegylated interferon-alpha.

Regulatory T cells as therapeutic targets in rheumatoid arthritis

Regulatory T cells (TREG) are a subset of CD4+ T cells with a critical role in the prevention of autoimmunity. Whether defects in TREG contribute to the pathogenesis of rheumatoid arthritis (RA) is unclear. However, a variety of approved and experimental drugs for RA may work, in part, by promoting the function or increasing numbers of TREG. Furthermore, animal studies demonstrate that direct injection of TREG ameliorates a wide range of experimental models of inflammatory and autoimmune diseases. Thus, cell-based therapy with TREG has the potential to produce durable disease remission in patients with RA.

Durable Long-Term Remission With Chemotherapy Alone for Stage II to IV Laryngeal Cancer

For patients with stage II to IV laryngeal cancer, radiation therapy (RT) either alone or with concurrent chemotherapy provides the highest rate of organ preservation but can be associated with functional impairment. Thus, we studied the use of induction chemotherapy with or without conservation laryngeal surgery (CLS). Our objectives were to study the sensitivity of laryngeal cancer to platinum-based chemotherapy alone and to highlight the efficacy of CLS in this setting. Thirty-one previously untreated patients with laryngeal cancer (T2-4, N0-1, M0), who were resectable with CLS, were enrolled. Patients received three to four cycles of paclitaxel, ifosfamide, and cisplatin (TIP) chemotherapy, and response was assessed histologically. Patients with partial response (PR) proceeded to CLS. Patients achieving pathologic complete response (pCR) received an additional three cycles of TIP and no other treatment. Thirty patients were assessable for response. With TIP chemotherapy alone, 11 patients (37%) achieved pCR, 10 of whom (33%) remain alive with durable disease remission and no evidence of recurrence over a median follow-up time of 5 years. Nineteen patients (63%) treated with TIP alone achieved PR. The overall laryngeal preservation (LP) rate was 83%, and only five patients (16%) required postoperative RT. No patient required a gastrostomy tube or tracheotomy. Chemotherapy alone in selected patients with T2-4, N0-1 laryngeal cancer can provide durable disease remission at 5 years. For patients with PR, CLS provides a high rate of LP. This prospective study suggests that chemotherapy alone may cure selected patients with laryngeal cancer, warranting further prospective investigation.

Unusual Fibrosclerotic Lesion of the Laryngotracheal Complex Presenting as Subglottic Stenosis

We present a case report that describes the pathology, presentation, and management complexities of an unusual, destructive fibrosclerotic lesion of the laryngotracheal complex. An otherwise healthy 21-year-old man presented with a 1-year history of progressive shortness of breath and stridor. The initial examination revealed a 3-cm, grade III subglottic stenosis. Nodular fibrosis of the strap muscles, laryngotracheal cartilages, and trachea was evident. Biopsies revealed dense peritracheal desmoplastic reaction with focal erosion of cartilage. However, features diagnostic for relapsing polychondritis, desmoid tumor, or orbital pseudotumor were absent. The disease progressed to involve severe stenosis and thickening of the trachea and main stem bronchi. Surgical and medical management of this unusual fibrosclerotic lesion did not ameliorate the disease process, but a recent encouraging response to tamoxifen citrate has been observed with improvements in vocal fold motion and activity levels. Prognosis and management experience for this unknown pathologic entity are absent in the literature. In this case, diffuse disease progression occurred despite surgical and medical management, but has been halted by tamoxifen therapy. The prospect of a durable response and disease remission is unknown.

High-dose chemotherapy and allogeneic immunotherapy

In this issue of The Lancet, Angelo Carella and colleagues1 present a novel study evaluating autologous followed by allogeneic haemopoietic cell transplantation (HCT) in women with metastatic breast cancer. This tandem transplant approach uses high-dose chemotherapy with autologous HCT to bring about short-term tumour cytoreduction, followed by an allogeneic HCT in a bid to achieve durable disease remission via immune-mediated graft-versus-tumour effects.

Definitive treatment of intermediate stage laryngeal squamous cell (SCC/L) cancer with chemotherapy (CT)

5533 Background: Surgery and/or radiotherapy (RT) are definitive local treatment modalities for intermediate stage SCC/L. Methods: We have evaluated paclitaxel (T) 175/mg/m2 day 1, ifosfamide (I) 1000mg/m2/days 1–3 (with mesna), and cisplatin (P) 60mg/m2 day 1 for previously untreated patients (pts) with SCC/L, stage T2 –4, N0 –1, M0. To be eligible, the primary tumor had to be considered resectable with conservation laryngeal surgery. After TIP x 3, pts achieving partial disease regression (PR) proceeded to surgery. Patients achieving a histologic complete response (CR) received an additional 3 CT cycles and no local treatment. A preliminary report was provided previously (FRK Proc ASCO #906, 2002). This is a report of more mature results with focus on CR patients treated with chemotherapy alone. Results: From 10/97 until 8/03, 29 patients (20 M, 9 F; median age 58 years, range 20–79) were entered. Tumor stage ranged from T2 N0 - T4 N1; median follow up is 36 months. Ten pts (34%) achieved CR and 17 (59%) PR after CT. CR patients were monitored monthly. Videostroboscopy will show tumor shrinkage, normalization of mucosa, and dramatic improvement in phonatory approximation in 5 of 5 pts with true vocal cord involvement. Two of 10 CR patients have developed local recurrence, with one living and disease-free after RT. Eight pts are alive and recurrence-free. Of the entire group of 29, 6 pts have developed recurrence (6 local/regional and 1 distant). Two patients have required total laryngectomy and 3 RT. Twenty-four of 29 pts are alive and disease-free. One patient died of a second primary cancer. Conclusions: Systemic chemotherapy for intermediate stage SCC/L provides durable disease remission in some pts. This favorable early experience suggests that SCC/L is potentially curable with systemic therapy. However, treatment of larynx cancer with chemotherapy as a single modality remains highly experimental. No significant financial relationships to disclose.

Definitive treatment of intermediate stage laryngeal squamous cell (SCC/L) cancer with chemotherapy (CT)

5533 Background: Surgery and/or radiotherapy (RT) are definitive local treatment modalities for intermediate stage SCC/L. Methods: We have evaluated paclitaxel (T) 175/mg/m2 day 1, ifosfamide (I) 1000mg/m2/days 1–3 (with mesna), and cisplatin (P) 60mg/m2 day 1 for previously untreated patients (pts) with SCC/L, stage T2 –4, N0 –1, M0. To be eligible, the primary tumor had to be considered resectable with conservation laryngeal surgery. After TIP x 3, pts achieving partial disease regression (PR) proceeded to surgery. Patients achieving a histologic complete response (CR) received an additional 3 CT cycles and no local treatment. A preliminary report was provided previously (FRK Proc ASCO #906, 2002). This is a report of more mature results with focus on CR patients treated with chemotherapy alone. Results: From 10/97 until 8/03, 29 patients (20 M, 9 F; median age 58 years, range 20–79) were entered. Tumor stage ranged from T2 N0 - T4 N1; median follow up is 36 months. Ten pts (34%) achieved CR and 17 (59%) PR after CT. CR patients were monitored monthly. Videostroboscopy will show tumor shrinkage, normalization of mucosa, and dramatic improvement in phonatory approximation in 5 of 5 pts with true vocal cord involvement. Two of 10 CR patients have developed local recurrence, with one living and disease-free after RT. Eight pts are alive and recurrence-free. Of the entire group of 29, 6 pts have developed recurrence (6 local/regional and 1 distant). Two patients have required total laryngectomy and 3 RT. Twenty-four of 29 pts are alive and disease-free. One patient died of a second primary cancer. Conclusions: Systemic chemotherapy for intermediate stage SCC/L provides durable disease remission in some pts. This favorable early experience suggests that SCC/L is potentially curable with systemic therapy. However, treatment of larynx cancer with chemotherapy as a single modality remains highly experimental. No significant financial relationships to disclose.