Radio-immunotherapy adjuvant to androgen deprivation therapy for prostate cancer, "Beyond the Abstract," by Raymond A. Clarke and Barry Allen

BERKELEY, CA (UroToday.com) - Systemic radioisotope treatments are indicated for patients with castrate resistant prostate cancer (CRPC). Both strontium-89 and samarium-153 alleviate metastatic bone pain but are used infrequently due to bone marrow toxicity, which limits subsequent chemotherapeutic and other options. Unlike these beta emitters, a phase III study of the alpha emitter Ra223 in 921 patients demonstrated an overall survival of 14 months for the treatment group compared with 11.2 months for placebo. Importantly, there was minimal bone marrow toxicity. Radium-223 (Alpharadin®) has now been approved by the FDA. However, it is a bone-seeking isotope and does not target soft tissue tumours.

The prostate specific membrane antigen (PSMA) is overexpressed in virtually all prostate cancers, with overexpression increasing with grade and in metastases. It is also expressed in the tumour neo-vasculature but not normal blood vessels and by small intestinal, proximal renal tubular, and salivary glandular cells but at levels 100 to1000-fold less than in prostate cancer.

An important and recent development in prostate cancer therapy has been the completion of a phase 2 trial of radio-immunotherapy for CRPC patients using a single dose of 177Lu-J591 conjugates. 177Lu is a low energy beta emitter of a 150 keV beta particle with an effective range of ~ 300 μm. Accurate tumour targeting and PSA responses were seen with evidence of dose response. Eleven percent of patients experienced a ≥50% decline in PSA; 36% experienced a ≥30% decline; and 60% experienced a significant PSA decline. One patient with a rapidly rising PSA pre-treatment (PSA doubling time 3.9 months) showed a 90% reduction in PSA. This phase 2 trial showed major decreases in PSA post-targeted beta therapy for 67% of subjects, with survival time doubling from 12 to 22 months at the maximum tolerance dose (MTD) of 70 mCi/m2. Overall, a single dose of 177Lu-J591 was efficacious and well tolerated with reversible myelosuppression.

The practical range of the 150 keV betas is ~300 μm, so non-targeted normal cells are spared and adverse events are reduced. But the linear energy transfer (LET) to targeted cancer cells from 177Lu is only ~0.5 keV/μm so toxicity is also very low. On the other hand, 213Bi is an alpha emitting radioisotope with an energy of 8.3 MeV, a range of 80 μm and LET ~100 keV/ μm. This is 200 times the LET for 177Lu betas. This means that if 213Bi is used to label J591, then cancer cell cytotoxicity will be very much greater than for 177Lu, but normal tissue exposure will be less because of the much shorter range. Comparative mouse studies have shown that similar or superior efficacy with reduced toxicity for 213Bi compared with 177Lu for radio-immunotherapy for peritoneal carcinomatosis and for radio-peptide therapy for prostate cancer.

The Lu177-J591 results set a new benchmark for the management of intractable, progressive, metastatic CRPC with only a single radio-immunotherapy treatment but at the maximum tolerance dose. To improve on these results, the same J591 antibody should be used in two complementary strategies.

  1. Conjugation of J591 to an ‘alpha’ rather than a ‘beta’ radio-isotope.
  2. Apply therapy earlier during ADT when residual disease is minimal and the PSA is at its nadir.

As a consequence, there is every expectation that improved results could be achieved with the radionuclides 213Bi and 225Ac, which decay by single or multiple alpha emission resp, and have far greater energy transfer rates and very short ranges.

Rationale:

  1. Androgen deprivation therapy dramatically decreases prostate cancer burden providing an invaluable window in time for a precision adjuvant therapy to eliminate residual disease before CRPC emerges.
  2. Phase 1 clinical trials demonstrate the specificity of the humanised J591 antibody to target prostate specific membrane antigen (PSMA) positive prostate cancer.
  3. A clinical trial indicates that J591-radionuclide conjugates can reverse CRPC progression.
  4. Androgen deprivation therapy using MDV3100 markedly up-regulates PSMA in prostate cancer cells, making J591-PSMA an ideal radio-immunotherapy target post- androgen deprivation therapy before CRPC emerges.
  5. PSMA is expressed by endothelial cells in tumour capillaries, so direct killing of these cells can be achieved with alpha radio-immunotherapy, closing capillaries and starving the tumour of oxygen and nutrients.

In summary, alpha radiation therapy with Ra223 is effective for palliation of CRPC, and ‘targeted beta radio-immunotherapy’ against PSMA is effective for systemic regression of disease. When combined, these two clinically proven approaches in the form of ‘targeted alpha radio-immunotherapy (TAT)’ represent a potent next generation therapy against prostate cancer indicating an urgent need to run a phase 1 and 2 clinical trial of systemic TAT for terminal CRPC patients.

Response to therapy would be by imaging with sequential MRI-PET scans that target PSMA. Immuno-response and radiation damage would be investigated in post-therapy tumour resections.

 

Written by:
Raymond A. Clarke and Barry Allen as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

School of Medicine, University of Western Sydney, Liverpool 2170, NSW, Australia.

Next-generation therapy for residual prostate cancer - Abstract

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