Immunotherapy in Prostate Cancer

Using a combination of drugs targeting multiple immune checkpoints in prostate cancer immunotherapy could be more effective than a single agent.

Highlights:

Prostate cancer is an immunologically cold cancer with hardly any T-cell response within the tumor microenvironment.
Prostate cancer is noted for its resistance to immunotherapy
Current study suggests that using combination of agents in immunotherapy might improve patient response, rather than using them singly.

T-cell activity against tumor cells and therefore patient response could be improved by using combination of agents, that are often ineffective when used alone, according to a recent study by The University of Texas MD Anderson Cancer Center led by Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology.

Reason Behind Study

The team of scientists wished to assess if tumor infiltration by immunocompetent T-cells could be enhanced in prostate cancer by combining Lupron, an anti-hormonal drug along with two courses of the negative immune checkpoint regulator (NCR) inhibitor ipilimumab prior to surgery, especially in patients with locally advanced disease.

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‘Employing checkpoint inhibitors such as ipilimumab and nivolumab together produce better responses than using singly, as they act at different points.’

Details and Findings of the Study

Seventeen patients participated in the Lupron-ipilimumab trial; 16 completed treatment followed surgery and one patient died of a cardiac complication before surgery. The important findings included the following:

Six patients displayed cancer progression while 10 were without evidence of
progression for at least 3.5 years
All 16 patients were living 3.5 years after surgery
All 17 showed an adverse immune reaction, with 8 of them experiencing the most serious grade 3 or 4 side effects, such as inflammation of the colon, pituitary gland or pancreas and elevated liver enzymes signifying injury. All of them were administered corticosteroids and other immune-suppressive agents.

Other Notable Observations From the Study

The other important observations during the current study have led the authors to believe that any immune response against a tumor must be looked at in its entirety rather than one immune response at a time. This is especially important because the immune response is a dynamic phenomenon and a single specific immune response may influence the subsequent responses in unexpected ways as outlined below:

Following treatment with ipilimumab, a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor

Immune T-cells come into the tumor milieu, but was followed by increased expression of other negative checkpoint regulators (NCRs) such as programmed death PD-1 and V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA) on T-cells that render the T-cells ineffective.
Expression of PD-1 and VISTA on macrophages ( a type of immune cells) were also increased, converting them into a M2 mode which promotes tumor growth and spread. The M1 mode is the one that stimulates immune response against the tumor.

"We concluded that driving T cells into the tumors would be step one, but then the next step would be to block PD-L1 and VISTA," Sharma said, suggesting that a combination of immunotherapeutic agents acting at different levels would have a better outcome.

These observations were made by analyzing samples of tumor tissue taken during and after treatment.

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"Understanding these changes using post-treatment or on-treatment biopsies is important to develop rational combination strategies for these immune-modulating drugs," she said. The presurgical clinical trials, also called window of opportunity trials, allow researchers to learn a lot from a small number of patients to guide the design of larger trials, Sharma said.

NCRs and Their Inhibitors

Negative checkpoint regulators (NCRs) are molecules that restrict the ability of the T-cells to effectively mount an immune attack against the tumor cells. Examples of negative checkpoint regulators include CTLA-4, PD-1 and VISTA expressed on T-cells.

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They act in different ways to decrease immune response. Under physiological conditions, these dampen T-cell activity, and are important in reducing inflammatory tissue damage and preventing autoimmune disease.

The 2 NCR inhibitors of interest include ipilimumab and nivolumab, widely researched.

NCR inhibitors are monoclonal antibodies against CTLA-4 (ipilimumab) or PD-1/PD-L1 (i.e. nivolumab) can activate the immune system, enhancing T-cell proliferation and activity against tumors.

Limitations of these Agents When Used Singly

As mentioned earlier, ipilimumab a CTLA-4 inhibitor increases T-cell entry into the tumor milieu, but at the same time increased the expression of 2 other NCRs, namely PD-1 and V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA), both of which once again down regulate the immune response against the tumor, making ipilimumab ineffective.
Interestingly, PD-1 inhibitors such as nivolumab cannot act if there is no T-cell infiltration within the tumor.

Future Research Plans

A clinical trial using ipilimumab and nivolumab combination is being planned by Dr Sharma and her team, and will enlist 90 volunteers nationally
An inhibitor for VISTA is undergoing phase I clinical trial to assess safety and dosage, but Sharma adds that the drug could also be combined in prostate cancer clinical trials once the Phase I is over.
The prostate cancer combination trial has protocols in place for recognizing and treating immune-related reactions that could be associated with ipilimumab and nivolumab.

In conclusion, this study has shown the way for how future research in immunotherapy may need to be approached to achieve optimal patient response.

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