Combining immune checkpoint inhibitors with radiation

Although anti–CTLA-4 and anti–PD-1 monoclonal antibodies ( mAbs ) may overcome T-cell suppression, T-cell activation depends on the engagement of the antigen receptor and the activating costimulation molecule CD28 expressed by mature APCs. For this reason, ionizing radiation, which can increase the production and presentation of tumor antigens not only by immunogenic cancers like melanoma but also by poorly immunogenic tumors, could augment the antitumor immune responses elicited by checkpoint immunomodulators anti–CTLA-4 and anti–PD-L1.

Radiation may augment immunomodulation by increasing CTL activity and the antigenic peptide pool.

Data from Deng and colleagues suggests that the combination of radiation and PD-L1 checkpoint blockade can synergistically reduce MDSCs.
Preclinical studies of murine models have demonstrated that various immunomodulators benefit from combinations with radiation through antigen release.
Postow and colleagues and Hiniker and colleagues each reported systemic responses in patients with melanoma treated with the combined regimen of anti–CTLA-4 mAb Ipilimumab and radiation, suggesting that coupling radiotherapy with immunotherapy may hold promise for inducing powerful, long-term abscopal effects in human patients.

Anti–CTLA-4 and radiation: preclinical findings

In the first preclinical study of the CTLA-4 blocker Ipilimumab in combination with radiation, Demaria and colleagues tested the hypothesis that Ipilimumab in combination with radiotherapy could elicit an abscopal antitumor response in a model of metastatic 4T1 breast cancer. In that study, tumors were injected in a primary and a distant site in mice and, as expected, Ipilimumab alone did not stop the progression of this poorly immunogenic tumor.
Similarly, although radiation alone delayed the growth of primary tumors, irradiated and control IgG-treated mice had similar overall survival rates owing to distant lung metastasis.
However, mice that received the combined regimen of CTLA-4 blockade and local radiotherapy showed both tumor shrinkage and inhibition of lung metastasis, which was associated with a significant survival advantage.

A similar study combining Flt3 therapy with radiation conducted with metastatic lung cancer cells in a tumor model produced the same results and suggested a long-term protective immune response.

In another study of breast cancer cells, Mastsumura and colleagues provided the first evidence that T-cell recruitment by proinflammatory chemotactic factors overcame previous blocks at the effector phase by poorly immunogenic tumors. This study confirmed that the expansion of vaccine-specific T cells via the use of monoclonal antibodies was not sufficient to elicit an antitumor immune response.

Rather, the chemokines and their receptors induced by ionizing radiation were needed to recruit tumor-specific CTLs to the target and, together with CTLA-4 blockers, break the pattern of immune escape and tumor tolerance by lymphocytes.

Ruocco and colleagues reported that in mice anti–CTLA-4 monoclonal antibodies used as monotherapy did not induce effective immune responses to poorly immunogenic tumors but it did when combined with local radiation, confirming the role of Ipilimumab and radiation in overcoming the tumor-elicited MHC class I–dependent arrest.

Although relatively immunogenic tumors such as melanoma have shown regression after antibody therapy, poorly immunogenic tumors may need the priming effects of radiotherapy to overcome blocks at the effector level. In other words, expansion of vaccine-specific T cells by CTLA-4 blockade alone may not be sufficient.

Anti–CTLA-4 and radiation: clinical findings

Postow and colleagues have described a patient whose metastatic melanoma regressed upon treatment with Ipilimumab and concurrent palliative radiotherapy. Specifically, a CT scan obtained several months after the patient had received a 28.5-Gy radiation dose ( given in three 9.5-Gy fractions ) to an area next to the spine revealed that masses elsewhere in the spleen and hilar lymph nodes had also regressed and eventually reached the point of stable minimal disease 10 months after the last dose of radiation.

This case led to a pilot study at a different institution by Hiniker and colleagues to combine Ipilimumab and concurrent radiotherapy for a patient with asymptomatic melanoma.
That patient was given a higher radiation dose ( 54 Gy in three fractions ) and showed a complete response in both the primary tumor and the metastatic lesions, which confirms the findings from preclinical studies indicating the importance of radiation dose.
These results have led to interest in combining Ipilimumab with radiation for treatment of other cancers, and a recent case report described a patient with NSCLC who also had an abscopal response.

In a phase I/II clinical study, Slovin and colleagues found that patients with metastatic castration-resistant prostate cancer responded to Ipilimumab plus radiation. In that study of 50 men given Ipilimumab ( four 10-mg/kg doses ) plus radiation ( 8-Gy fractions to each lesion for 3 weeks ), 1 patient experienced a complete response, 6 had disease stabilization, and 8 showed declines in prostate-specific antigen levels that mirrored findings from previous preclinical studies.
This combination is now being tested in phase III trials, and interest has been spurred in its use to treat other types of tumors.

Anti–PD-1 and radiation: preclinical findings

With the anticancer efficacy of CTLA-4 blockers, anti–PD-1/-PD-L1 monoclonal antibodies have drawn much interest for their potential use in lung or colon cancer and in combination with CTLA-4 blockade for melanoma.
The mechanism by which radiation augments the therapeutic effects of the anti–PD-1/PD-L1 monoclonal antibodies was elucidated in a preclinical study of triple-negative breast cancer.
In this study, neither anti–PD-1 monoclonal antibodies nor radiation when given alone was effective in a murine model of triple-negative breast cancer. However, the addition of anti–PD-1 monoclonal antibodies enhanced the curative capacity of radiotherapy and alpha-CD137 ( an agonist antibody for costimulatory molecule 4-1BB ) against both established tumors and secondary tumor challenge, indicating that the combined regimen conferred antitumor immune responses and memory.

Moreover, a subset of tumor-specific CD8+ T cells expressing CD137, PD-1, or both was found to persist in the irradiated tumor tissues, suggesting that the synergistic effect of this triple combination was mediated by an activation or escalation of CD8+ T cell–mediated antitumor responses.

Although the PD-1 axis did not seem to be the main contributor to the metastatic and neoplastic capability of AT-3 tumors, PD-1 signaling within those tumors was critical for limiting the effectiveness of alpha-CD137 / alpha-CD40 immunotherapy, with or without adjuvant radiotherapy.

Indeed, the combination of alpha-CD137, anti–PD-1, and radiation showed greater efficacy ( 40% rejection ) than anti–PD-1 or radiation, given alone or in combination.
Furthermore, in mice whose tumors regressed completely at the primary site when treated with this triple combination, growth of the AT-3 tumors at distant sites was also impaired, indicating an abscopal effect.
This effect was dependent on the presence of CD8+ T cells, as mice lacking CD4+ T cells showed the abscopal effect, but CD8+ T cell–depleted mice did not.

Results of a preclinical study of murine intracranial glioma treated with anti–PD-1 monoclonal antibodies plus radiotherapy showed not only long-term survival of the treated mice, but also robust systemic immunologic memory in the surviving mice, as they were able to reject a secondary challenge of glioma cells injected in the flank.
Specifically, median survival periods were similar for control mice ( 25 days ) and mice given only anti–PD-1 monoclonal antibodies ( 27 days ) or radiation ( 28 days ).

However, the combination of radiation plus anti–PD-1 therapy extended the median survival to 53 days ( P less than 0.05 by log-rank Mantel–Cox test ), and 15% to 40% of mice survived more than 180 days after treatment.
The combination therapy increased tumor infiltration by CD8+ CTLs and decreased the number of CD4+ Tregs.

Finally, in a test of immunologic memory, naïve and long-term surviving mice were injected in the flanks with GL261-luc cells. All 8 naïve mice died from the growth of the challenged glioma cells, whereas mice that received prior treatment with the combined regimen rejected the glioma challenge.

On the basis of the results of these preclinical studies, several clinical trials have been initiated to assess the efficacy of combining anti–PD-1 immunotherapy with radiotherapy. ( Xagena )

Tang C et al, Cancer Immunol Res 2014 2; 831



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