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Moderate activity of the endoplasmic reticulum (ER) stress response system exerts anti-apoptotic function and supports tumor cell survival and chemoresistance, whereas its more severe aggravation may exceed the protective capacity of this system and turn on its pro-apoptotic module. In this study, we investigated whether the combination of two pharmacologic agents with known ability to trigger ER stress via different mechanisms would synergize and lead to enhanced tumor cell death. We combined the HIV protease inhibitor nelfinavir (Viracept) and the cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex) and investigated their combined effect on ER stress and on the viability of breast cancer cells. We found that this drug combination aggravated ER stress and caused pronounced toxicity in human breast cancer cell lines, inclusive of variants that were highly resistant to other therapeutic treatments, such as doxorubicin, paclitaxel, or trastuzumab. The anti-tumor effects of celecoxib were mimicked at increased potency by its non-coxib analog, 2,5-dimethyl-celecoxib (DMC), but were substantially weaker in the case of unmethylated-celecoxib (UMC), a derivative with superior COX-2 inhibitory efficacy. We conclude that the anti-tumor effects of nelfinavir can be enhanced by celecoxib analogs in a COX-2 independent fashion via the aggravation of ER stress, and such drug combinations should be considered as a beneficial adjunct to the treatment of drug-resistant breast cancers.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: The current median survival for patients with metastatic NSCLC is ∼7 mos. Novel approaches, such as immunotherapy, are warranted. Recent success with immune checkpoint blockade in metastatic NSCLC has been reported for blocking antibodies to PD-L1 and PD-1, but not to CTLA-4. We demonstrated pre-clinically that radiotherapy (RT) incites immunogenic cell death and enables cross-priming of tumor specific effector T-cells by DCs to eliminate in field and abscopal (ab-scopus, away from the target) metastases. We reported the 1st complete abscopal response in a patient with metastatic NSCLC, treated with RT and ipilimumab, who remains disease free >2.5 yrs. Thus, we initiated a prospective clinical trial (NYU S14-00208) to test this regimen in similar patients. We report the preliminary results on eight evaluable patients, who completed treatment. Methods: Eligible patients had chemo-resistant metastatic NSCLC, progressed on at least 1 chemotherapy regimen, ≥2 measurable lesions, ECOG PS ≤1, life expectancy >3 mos, non-steroid dependent, and no active intracranial disease. The first cohort consisted of patients treated with 6Gy x5 plus ipilimumab (3mg/kg x4 cycles). Patients were evaluated with pre and post-treatment (day 81 from treatment inception) PET/CTs. Results: Eight patients treated are currently evaluable (Table). The median prior chemotherapy regimens was 2, prior RT courses was 1.5, and time from diagnosis of metastatic disease was 6.75 mos. Conclusion: Metastatic NSCLC is only marginally responsive to CTLA-4 blockade alone; yet, our preliminary data suggest that with the addition of RT, objective responses are more common. This novel approach to treating metastatic NSCLC holds tremendous promise. The trial continues the planned accrual of 29 patients. | # | Time from Metastatic Disease (Mos) | # of Prior Treatments | Irradiated Site | irRECIST PET/CT | Best Abscopal Response | Maximum Toxicity | |:-- | ---------------------------------- | --------------------- | ---------------------------------------- | --------------- | -------------------------- | ---------------- | | 1 | 4.3 | 3 chemo | L para-spinal mass | SD (-37.5%) | L hilar lymph node | G2 fatige | | | | 2 RT | | | PR (-68%) | | | 2 | 38.5 | 4 chemo | L fissural nodule | SD (+7.2%) | L diaphragmatic lymph node | G2 rash | | | | 3 RT | | | SD (-16.7%) | | | 3 | 0.9 | 2 chemo | R anterior pleural nodule | CR (-100%) | R pleural nodule | G2 rash | | | | 2 RT | | | CR (-100%) | | | 4 | 3.5 | 1 chemo | R hilum | CR (-100%) | L Sclav lymph node | G3 (ALT) | | | | 1 RT | | | CR (-100%) | | | 5 | 7 | 1 chemo | R upper lobe nodule | POD (+57%) | R Sclav lymph node | G1 pruritis | | | | | | | SD (+10%) | | | 9 | 18.4 | 2 chemo | Porta hepatis lymph nodes | SD (+15%) | Peripancreatic lymph node | G1 fatigue | | | | 2 RT | | | PR (-65%) | | | 10 | 16 | 2 chemo | R lower lobe, posterior to the hilum | POD (+47.9%) | R peri-hilar lymph node | G2 pruritis | | | | | | | SD (+10%) | | | 11 | 6.5 | 1 chemo | Posterior L lower lobe subpleural nodule | POD (+479%) | Medial L lung base | G2 dyspnea | | | | | | | SD (-6.25%) | | Table: CR = complete response, PR = partial response, SD = stable disease, POD = progression of disease Citation Format: Encouse B. Golden, Abraham Chachoua, Maria Fenton-Kerimian, Sandra Demaria, Silvia C. Formenti. Abscopal responses in patients with refractory metastatic NSCLC treated with concurrent radiotherapy and CTLA-4 immune checkpoint blockade: evidence for the in situ vaccination hypothesis of radiotherapy . [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 244. doi:10.1158/1538-7445.AM2015-244

Traditional factors of DNA damage and tumor cell kill, described by the “4 R’s” of radiobiology (Reassortment, Reoxygenation, Repair, and Repopulation) fall short in explaining the role of immunity in hosts treated with radiotherapy. We propose a “5th R,” (immune-mediated) Rejection, which recognizes the contribution of the immune system to the antineoplastic effects of radiotherapy.