Advances in Immunotherapy

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Trial Shows Safety of Prostvac Vaccine Therapy for Prostate Cancer Patients

 

An international team of researchers has shown that a specific vaccine therapy that activates a patient’s immune response can be safely administered to prostate cancer patients.

 

The Phase II clinical study, published in the European Urology journal, evaluated this new vaccine in patients who had advanced prostate cancer diagnosed by increased prostate-specific antigen (PSA) and no visible metastasis, and whose cancer was resistant to hormone therapy. Furthermore, patients had already undergone surgery or radiation therapy.

 

In the first part of the study, patients received PROSTVAC-V/TRICOM and PROSTVAC-F/TRICOM. The first is a vaccine that originates from a modified vaccinia virus that produces the PSA protein, helping to direct the patient’s immune response towards the PSA present in their prostate cancer cells. Additionally, this virus is genetically modified to produce 3 other proteins that augment the immune system’s capacity to locate and destroy cancer cells.

 

PROSTVAC-F derives from the fowlpox virus and is endowed with the same genetic profile as PROSTAC-V, however it is administered several times to enhance the patient’s immune system.

 

Men who enrolled in the trial were treated with one cycle of PROSTVAC-V/TRICOM followed by PROSTVAC-F/TRICOM for multiple cycles in combination with GM-CSF, a protein known to augment and activate some white blood cells.

 

The results showed that after the first six months of therapy, 63% of patients had no disease progression and minimal toxic side effects.

 

Before the treatment, the median PSA velocity was 0.13 log (PSA)/month, when compared to median post-treatment velocity of 0.09 log (PSA)/month.

 

In the second half of the trail, patients received hormone therapy together with the PROSTVAC-VF/TRICOM combination, with 74% of subjects experiencing a complete response after seven months of follow up.

 

“Previous studies by the ECOG-ACRIN Cancer Research Group and others have shown it is optimal to explore agents like PROSTVAC that harness the body’s own defenses in shutting down cancer. With our current findings demonstrating the safe use of combination vaccine therapy earlier in the course of prostate cancer progression, we are laying the groundwork for future immunotherapy options for this patient population,” lead author Robert S. DiPaola, MD, Cancer Institute of New Jersey Director, said in a news release.

 

 

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An optimistic picture of where immunotherapy is heading - and how fast! (extract from 'Practice Update', 11/2/2015, Elsevier)

 

written by

 

 Isabel Cunningham MD    Axel Grothey MD    Lee S. Schwartzberg MD, FACP

Indisputably, the oncology story of the year was immunotherapy taking its place as a new pillar of treatment, complementing surgery, chemotherapy, radiotherapy, and biological therapy. An explosion of basic and translational science has confirmed the time-honored concepts that the host immune system is locked in an ongoing tug-of-war with tumors, which have multiple methods of evading immune destruction. The major mechanisms behind immunotolerance have been elucidated, consisting of a number of different processes in a complex system that, now identified, can be targeted to stimulate immune clearance of cancer.

 

 

 

 

 

 

 

 

 

 

 

Immunotherapy is not new: Interferon alpha and interleukin 2 have been in use for decades, and Coley’s toxin led to remarkable remissions in the nineteenth century. However, these broadly active molecules with pleotropic effects trigger vast swaths of immune reactions, leading to severe and multiple toxicities and only a small percentage of selected tumors eradicated. More recently, greater appreciation of the role of cytotoxic T cells has led to the development of other drugs like ipilimumab, which inhibits CTLA4, an immune checkpoint–blocking molecule preventing priming of a tumoricidal T-cell response. Ipilimumab was approved in 2011 for melanoma based on encouraging response data in this difficult-to-treat tumor. This year, reports of long-term results for patients with advanced melanoma previously treated with ipilimumab revealed that there is a significant number of patients—approximately 20% of trial participants—who enjoy long-term disease-free survival. What is more remarkable is that these patients received only a few months of therapy, yet the immune response is maintained for years, even a decade after treatment.

 

 

 

 

 

 

 

 

 

 

 

 

Even more impressive were the results of monoclonal antibodies directed against PD1, the programmed death receptor expressed by T cells, which, when activated, cause the T-cell response to go forward. PD1 activation can be blocked by the ligands PD-L1 and PD-L2, which are found on tumor cells and inflammatory cells. This ligand–receptor interaction prevents the destruction of the cancer and is a protective event. The PD1 antibodies pembrolizumab and nivolumab activate PD1 and cause tumor cell death. Both drugs were approved this year based on remarkable responses in previously heavily treated melanoma patients. Nivolumab compared with dacarbazine in the front-line treatment of metastatic melanoma markedly improved response rates and survival, with 1-year survival of 72.9%, a figure previously unheard of in this lethal disease.What is most interesting about PD1 antibodies specifically, and immunotherapy in general, is that the mechanism is not limited to one tumor or one tissue type.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Therefore, good results have been demonstrated in many different types of tumors. To date, heavily pretreated patients with squamous cell non–small cell lung cancer showed a 15% response rate and a median overall survival of 8.2 months to nivolumab. A remarkable result presented at the recent ASH 2014 meeting was obtained with PD1 antibody in relapsed or refractory Hodgkin’s lymphoma, with an astonishing 87% response rate in patients who had failed transplant, chemotherapy, and antibody drug conjugates. Non-Hodgkin’s lymphoma also displays high sensitivity to PD1, showing that the response is not limited to solid tumors. Other studies have shown intriguing response rates in bladder cancer, non-squamous non–small cell lung cancer, and even triple-negative breast cancer.

 

While much needs to be learned about factors predicting response and resistance to immunotherapy, the results to date are paradigm-shifting. Patients with diseases with terrible prognoses are now the beneficiaries of a new therapeutic approach that creates clinically meaningful improvement. Combination therapy trials of multiple immunotherapy agents are progressing and hold the promise of even greater benefit for patients across a large spectrum of tumor types.

Watch this space!