Due to imbalances between vascularity and cellular growth patterns, the tumour microenvironment harbours multiple metabolic stressors including hypoxia and acidosis, which have significant influences on remodelling both tumour and peritumoral tissues. These stressors are also immunosuppressive and can contribute to escape from immune surveillance. Understanding these effects and characterizing the pathways involved can identify new targets for therapy and may redefine our understanding of traditional anti-tumour therapies. In this review, the effects of hypoxia and acidosis on tumour immunity will be summarized, and how modulating these parameters and their sequelae can be a useful tool for future therapeutic interventions is discussed.

Background Cancer progression is governed by evolutionary dynamics in both the tumour population and its host. Since cancers die with the host, each new population of cancer cells must reinvent strategies to overcome the host’s heritable defences. In contrast, host species evolve defence strategies over generations if tumour development limits procreation. Methods We investigate this “evolutionary arms race” through intentional breeding of immunodeficient SCID and immunocompetent Black/6 mice to evolve increased tumour suppression. Over 10 generations, we injected Lewis lung mouse carcinoma cells [LL/2-Luc-M38] and selectively bred the two individuals with the slowest tumour growth at day 11. Their male progeny were hosts in the subsequent round. Results The evolved SCID mice suppressed tumour growth through biomechanical restriction from increased mesenchymal proliferation, and the evolved Black/6 mice suppressed tumour growth by increasing immune-mediated killing of cancer cells. However, transcriptomic changes of multicellular tissue organisation and function genes allowed LL/2-Luc-M38 cells to adapt through increased matrix remodelling in SCID mice, and reduced angiogenesis, increased energy utilisation and accelerated proliferation in Black/6 mice. Conclusion Host species can rapidly evolve both immunologic and non-immunologic tumour defences. However, cancer cell plasticity allows effective phenotypic and population-based counter strategies.

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BACKGROUND: The tumor microenvironment is acidic, which inhibits the activity of weakly basic drugs such as doxorubicin. In order to test whether neutralization of tumor acidity can improve survival in pancreatic cancer-bearing mice treated with doxorubicin, we tested doxorubicin in combination with L-DOS47. L-DOS47 is a novel therapy comprised of urease conjugated to an antibody against CEACAM6, which raises the pH in the tumor microenvironment by converting endogenous urea to NH3 and CO2. Our findings demonstrate that raising tumor pH with L-DOS47 can improve responses to chemotherapy. As L-DOS47 is currently in clinical testing for NSCLC, current study is clinically relevant. METHODS: Panc02 pancreatic cancer cell line (obtained from Emmanual Zervos, East Carolina University, Greenville, NC) was infected to express CEACAM6. 1 x 106 CEACAM6 Panc02 Clone were injected subcutaneously in the right flank of C57BL/6 mice. Four days later, tumor sizes were measured with calipers and mice were forcibly randomized into 3 groups (10 mice/ group). The 3 groups were treated with Doxorubicin only; L-DOS47 4 hours before Doxorubicin; and L-DOS47 24 hours before Doxorubicin. The rationale for different timings were that MRS measurements of tumor pH indicate that tumor alkalization has been observed both 4 and 24 hours following injection of L-DOS47. Treatments were begun immediately after randomization. Doxorubicin (2.5 mg/kg) was injected every 3-4 days and L-DOS47 (90 μg/kg) was injected either 4 or 24 hour prior to Doxorubicin i.v. RESULTS: All mice were humanely euthanized when tumors either reached 2000 mm3 (endpoint) or had serious ulcerations. For the tumors hadn’t reached to the endpoint due to serious ulcerations, times to reach the endpoint were estimated using a mathematical model that describes exponential tumor growth. Kaplan Meier survival curves were generated for each treatment group. According to Log-rank Mantel-Cox, Log-rank for trend, Gehan-Breslow-Wilcoxon test observed mice group survival was significantly different from each other (p<0.008 for all 3 tests). The probability of survival of mice group treated with L-DOS47 either 4 or 24 hours before doxorubicin was significantly better than doxorubicin only group. CONCLUSION: In this study we have observed that neutralizing tumor pH can improve the effect of chemotherapy in vivo. This is consistent with prior observations where neutralization with bicarbonate improved the response to chemotherapy via reversal of an ion-trapping effect [1]. The current work is significant, however, as L-DOS47 can be used clinically, whereas bicarbonate cannot. References: [1] Raghunand, N., Mahoney, B.P., and Gillies, R.J.: ‘Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents’, Biochem Pharmacol, 2003, 66, (7), pp. 1219-1229. Citation Format: Sultan Damgaci, Heman Chao, Marni D. Uger, Arig Ibrahim-Hashim, Eunjung Kim, Pedro Pedro M. Enriquez-Navas, Dominique Abrahams, Alexander R. Anderson, Albert Guvenis, Robert J. Gillies. Improving survival in pancreatic cancer using Doxorubicin in combination with L-DOS47 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1231.

312 Background: Radium-223 dichloride (Xofigo) is an FDA-approved radionuclide used to treat symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known visceral metastases. Outside of clinical trial, the benefits of Radium-223 dichloride (Ra-223) in the treatment of CRPC have not yet been fully delineated in real life setting. Therefore, the purpose of this study was to evaluate the outcome of patients with CRPC who were treated with Ra-223, especially studying the variables associated with completion of 6 cycles of therapy. Methods: A total of 114 patients with CRPC and bone metastases referred for treatment with Ra-223 between March 2010 and February 2018 were identified for retrospective analysis. A chart review was conducted to analyze clinical characteristics, treatments, and outcomes including radiologic bone scans. Categorical variables were compared using Chi-square and independent student t test, and survival rates were generated using Kaplan-Meier analysis. Multivariate analysis (MVA) Cox proportional hazard ratios (HR) model was used in the assessment of OS and PFS. Results: Of the 114 patients referred for treatment, the overall median OS was 12.6 months. In MVA, improved OS was most strongly associated with completion of all six doses (p < 0.001). Median OS for the 56 patients who received full treatment was 24 months, while median OS for the 107 patients who did not complete treatment was 5.9 months. In univariate analysis, treatment completion was significantly associated with prior Sipuleucel-T (p = 0.002), concurrent Denosumab (p = 0.027), and baseline PSA < 30 ng/mL (p = 0.004). Conclusions: Completion of treatment with Ra-223 is a significant factor associated with improved OS. Therefore it is clinically important to delineate which patients are to the most appropriate candidates to complete treatment. Factors notable for treatment completion suggest patients might benefit from initiating Ra-223 treatment after receiving Sipuleucel-T and while their PSA remains low. Further consideration should be given to the sequence of Ra-223 in clinical practice, including use of concurrent Abiraterone and Enzalutamide.